Hepatitis C virus inhibitors

ABSTRACT

The invention provides compounds of formulas (I) or (II): 
                         
wherein the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are inhibitors of replication of the hepatitis C virus. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat hepatitis C viral infections, and processes and intermediates useful for preparing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/637,956, filed on Apr. 25, 2012 and 61/773,977, filed on Mar. 7,2013, the disclosures of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is directed to compounds useful as inhibitors ofreplication of the hepatitis C virus (HCV). The invention is alsodirected to pharmaceutical compositions comprising such compounds,methods of using such compounds to treat HCV infection, and processesand intermediates useful for preparing such compounds.

2. State of the Art

Recent estimates place the number of people infected with the hepatitisC virus (HCV) worldwide at more than 170 million, including 3 millionpeople in the United States. The infection rate is thought to be roughly4 to 5 times that of the human immunodeficiency virus (HIV). While insome individuals, the natural immune response is able to overcome thevirus, in the majority of cases, a chronic infection is established,leading to increased risk of developing cirrhosis of the liver andhepatocellular carcinomas. Infection with hepatitis C, therefore,presents a serious public health problem.

Prior to mid-2011, the accepted standard of care for HCV involved theuse of a pegylated interferon which is believed to act by boosting thebody's immune response, together with ribavirin. Unfortunately, thecourse of treatment is lengthy, typically 48 weeks, often accompanied byserious adverse side effects, including depression, flu-like symptoms,fatigue, and hemolytic anemia, and ineffective in up to 50% of patients.In mid-2011, two HCV protease inhibitors were approved in the UnitedStates to be used in combination with interferon and ribavirin. Althoughbetter cure rates have been reported, the course of therapy is stilllengthy and accompanied by undesirable side effects. Accordingly, thereremains a serious unmet need in HCV treatment.

The virus responsible for HCV infection has been identified as apositive-strand RNA virus belonging to the family Flaviviridae. The HCVgenome encodes a polyprotein that during the viral lifecycle is cleavedinto ten individual proteins, including both structural andnon-structural proteins. The six non-structural proteins, denoted asNS2, NS3, NS4A, NS4B, NS5A, and NS5B have been shown to be required forRNA replication. In particular, the NS5A protein appears to play asignificant role in viral replication, as well as in modulation of thephysiology of the host cell. Effects of NS5A on interferon signaling,regulation of cell growth and apoptosis have also been identified.(Macdonald et al., Journal of General Virology (2004), 85, 2485-2502.)Compounds which inhibit the function of the NS5A protein are expected toprovide a new approach to HCV therapy.

SUMMARY OF THE INVENTION

In one aspect, the invention provides novel compounds which inhibitreplication of the HCV virus.

Accordingly, the invention provides a compound of formula (I):

or of formula (II):

wherein

the dashed bond in formula (II) may be present or absent;

W is selected from

G is

R¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, phenyl, C₃₋₆cycloalkyl,heterocycle, and heteroaryl, wherein C₁₋₆alkyl is optionally substitutedwith —OR^(a), amino, —SR^(e), heterocycle, or heteroaryl, C₁₋₆alkoxy isoptionally substituted with —OR^(a), and heterocycle is optionallysubstituted with —OR^(a), amino, or —C(O)OC₁₋₆alkyl, or with one or twoC₁₋₃alkyl;

R² is selected from hydrogen and C₁₋₆alkyl;

R³ is selected from hydrogen, C₁₋₆alkyl, —C(O)OC₁₋₆alkyl,—C(O)NR^(b)R^(c), —C(O)C₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl;

R⁴ is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, and halo;

R⁵ is selected from hydrogen, C₁₋₆alkyl, —OR^(d), halo, —S(O)C₁₋₃alkyl,—S(O)₂C₁₋₃alkyl, NR^(b)R^(c), —CN, and —C(O)NR^(b)R^(c);

R⁶ is independently selected from hydrogen, C₁₋₆alkyl, and halo;

R⁷ is selected from halo, C₁₋₃alkyl, and C₁₋₃alkoxy wherein C₁₋₃alkyland C₁₋₃alkoxy are optionally substituted with one, two, three, four, orfive halo;

R⁸ is C₁₋₃alkyl, optionally substituted with —OR^(d);

R⁹ is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, —NR^(f)R^(g),heteroaryl, heterocycle, and —CH₂-heteroaryl;

-   -   wherein:    -   C₁₋₆alkyl is optionally substituted with one or two substituents        independently selected from —OR^(h), —NR^(j)R^(k),        —NHC(O)C₁₋₃alkyl, —NHC(O)C₃₋₆cycloalkyl, and —NHC(O)OC₁₋₃alkyl;    -   C₁₋₆alkoxy is optionally substituted with —OR^(h);    -   any C₃₋₆cycloalkyl is optionally substituted with one, two, or        three substituents independently selected from C₁₋₃alkyl, halo,        —OR^(h), and —CD₃;    -   any heterocycle is optionally substituted with one, two, or        three substituents independently selected from C₁₋₃alkyl, halo,        —C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl, —C(O)C₃₋₆cycloalkyl,        —C(O)NHC₁₋₆alkyl, and —C(O)NHC₃₋₆cycloalkyl;        -   wherein any —C(O)C₁₋₆alkyl is optionally substituted with            —NHC(O)OC₁₋₃alkyl, —OR^(h) or —NR^(j)R^(k),    -   any heteroaryl is optionally substituted with one or two        C₁₋₃alkyl;

R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(h), R^(j), and R^(k) areeach independently hydrogen or C₁₋₃alkyl;

R^(g) is selected from hydrogen, C₁₋₆alkyl, and C₃₋₆cycloalkyl;

R¹⁰ is hydrogen, halo, or C₁₋₃alkyl substituted with one, two, or threehalo or with —OR^(d);

R¹¹ is selected from hydrogen, C₁₋₆alkyl, and halo;

R¹² is hydrogen, or R¹¹ and R¹² taken together form —CH₂—;

A_(m) is —NHC(O)— or —C(O)NH—

a is 0, 1, or 2; and

b is 0, 1 or 2;

or a pharmaceutically-acceptable salt or stereoisomer thereof.

As used hereinafter, the phrase “compound of formula (I)” means acompound of formula (I) or a pharmaceutically acceptable salt thereof;i.e., this phrase means a compound of formula (I) in free base form orin a pharmaceutically acceptable salt form unless otherwise indicatedand similarly, for “compound of formula (II)”.

The invention also provides a pharmaceutical composition comprising acompound of the invention and a pharmaceutically-acceptable carrier. Inaddition, the invention provides a pharmaceutical composition comprisinga compound of the invention, a pharmaceutically-acceptable carrier andone or more other therapeutic agents useful for treating hepatitis Cviral infections.

The invention also provides a method of treating a hepatitis C viralinfection in a mammal, the method comprising administering to the mammala therapeutically effective amount of a compound or of a pharmaceuticalcomposition of the invention. In addition, the invention provides amethod of treating a hepatitis C viral infection in a mammal, the methodcomprising administering to the mammal a compound or a pharmaceuticalcomposition of the invention and one or more other therapeutic agentsuseful for treating hepatitis C viral infections. Further, the inventionprovides a method of inhibiting replication of the hepatitis C virus ina mammal, the method comprising administering a compound or apharmaceutical composition of the invention.

In separate and distinct aspects, the invention also provides syntheticprocesses and intermediates described herein, which are useful forpreparing compounds of the invention.

The invention also provides a compound of the invention as describedherein for use in medical therapy, as well as the use of a compound ofthe invention in the manufacture of a formulation or medicament fortreating a hepatitis C viral infection in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

Among other aspects, the invention provides inhibitors of HCVreplication of formula (I), pharmaceutically-acceptable salts thereof,and intermediates for the preparation thereof. The followingsubstituents and values are intended to provide representative examplesof various aspects of this invention. These representative values areintended to further define such aspects and are not intended to excludeother values or limit the scope of the invention.

In a specific aspect, R¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, phenyl,C₃₋₆cycloalkyl, heterocycle, and heteroaryl, wherein C₁₋₆alkyl isoptionally substituted with —OR^(a), amino, —SR^(e), heterocycle, orheteroaryl, C₁₋₆alkoxy is optionally substituted with —OR^(a), andheterocycle is optionally substituted with —OR^(a), amino, or—C(O)OC₁₋₆alkyl, or with one or two C₁₋₃alkyl.

In another specific aspect, R¹ is selected from C₁₋₆alkyl, phenyl, andheterocycle, wherein C₁₋₆alkyl is optionally substituted with —OR^(a),and heterocycle has six ring atoms and is optionally substituted with—OR^(a) or amino or with one or two methyl.

In another specific aspect, R¹ is selected from C₁₋₆alkyl, phenyl, andtetrahydropyranyl, wherein C₁₋₆alkyl is optionally substituted with—OR^(a); wherein R^(a) is hydrogen or C₁₋₃alkyl.

In a specific aspect, R¹ is C₁₋₃alkyl.

In another specific aspect, R¹ is isopropyl.

In yet another specific aspect, R¹ is phenyl.

In still another specific aspect, R¹ is tetrahydropyranyl.

In still another specific aspect, R¹ is tetrahydropyran-4-yl.

In a specific aspect, R² is hydrogen or C₁₋₆alkyl.

In other specific aspects, R² is hydrogen or C₁₋₃alkyl; or R² ishydrogen.

In a specific aspect, R³ is selected from hydrogen, C₁₋₆alkyl,—C(O)OC₁₋₆alkyl, —C(O)NR^(b)R^(c), —C(O)C₃₋₆cycloalkyl, and—S(O)₂C₁₋₃alkyl; or R² and R³ together with the nitrogen atom to whichthey are attached form a heterocycle;

In another specific aspect, R³ is selected from hydrogen, C₁₋₆alkyl,—C(O)OC₁₋₆alkyl, —C(O)NR^(b)R^(c), —C(O)C₃₋₆cycloalkyl, and—S(O)₂C₁₋₃alkyl;

In another specific aspect, R³ is selected from hydrogen, C₁₋₆alkyl, and—C(O)OC₁₋₆alkyl.

In yet another specific aspect, R³ is —C(O)OC₁₋₃alkyl.

In a specific aspect, R¹ is C₁₋₆alkyl, R² is hydrogen, and R³ is—C(O)OC₁₋₆alkyl.

In another specific aspect, R¹ is isopropyl, R² is hydrogen, and R³ is—C(O)OCH₃.

In yet other specific aspects, R¹ is phenyl and R² and R³ are eachC₁₋₃alkyl; or R¹ is phenyl, R² is hydrogen, and R³ is —C(O)OC₁₋₃alkyl;or R¹ is tetrahydropyranyl, R² is hydrogen, and R³ is —C(O)OC₁₋₃alkyl.

In a specific aspect, R⁴ is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, andhalo;

In a specific aspect, R⁴ is C₁₋₆alkyl or C₃₋₆cycloalkyl;

In another specific aspect, R⁴ is C₁₋₆alkyl.

In another specific aspect, R⁴ is C₃₋₆cycloalkyl.

In another specific aspect, R⁴ is methyl or cyclopropyl.

In a specific aspect, R⁵ is selected from hydrogen, C₁₋₆alkyl, —OR^(d),halo, —S(O)C₁₋₃alkyl, —S(O)₂C₁₋₃alkyl, NR^(b)R^(c), —CN, and—C(O)NR^(b)R^(c).

In another specific aspect, R⁵ is selected from hydrogen, C₁₋₆alkyl, and—OR^(d);

In a specific aspect, R⁵ is hydrogen or C₁₋₃alkyl.

In another specific aspect, R⁵ is methyl.

In a specific aspect, R⁶ is independently selected from hydrogen,C₁₋₆alkyl, and halo.

In another specific aspect, R⁶ is hydrogen or C₁₋₃alkyl.

In another specific aspect, R⁶ is methyl.

In a specific aspect, R⁷ is selected from halo, C₁₋₃alkyl, andC₁₋₃alkoxy wherein C₁₋₆alkyl and C₁₋₆alkoxy are optionally substitutedwith one, two, three, four, or five halo.

In another specific aspect R⁷ is selected from halo, C₁₋₃alkyl, andC₁₋₃alkoxy wherein C₁₋₆alkyl and C₁₋₆alkoxy are substituted with one,two, or three halo.

In yet another specific aspect, R⁷ is selected from fluoro, chloro,—CF₃, and —OCF₃.

In a specific aspect, R⁸ is C₁₋₃alkyl, optionally substituted with—OR^(d); wherein R^(d) is hydrogen or C₁₋₃alkyl.

In a specific aspect, R⁸ is C₁₋₃alkyl.

In another specific aspect, R⁸ is methyl.

In a specific aspect, R⁹ is defined as in formulas (I) and (II).

In another specific aspect, R⁹ is selected from C₁₋₆alkyl,C₃₋₆cycloalkyl, C₁₋₆alkoxy, —NR^(f)R^(g), heteroaryl, and heterocycle;wherein any heteroaryl or heterocycle has 5 or 6 ring atoms; C₁₋₆alkylis optionally substituted with one or two substituents independentlyselected from —OR^(h), —NR^(j)R^(k), —NHC(O)C₁₋₃alkyl, and—NHC(O)OC₁₋₃alkyl; any C₃₋₆cycloalkyl is optionally substituted with oneor two substituents independently selected from C₁₋₃alkyl and halo; anyheterocycle is optionally substituted with one, two, or threesubstituents independently selected from C₁₋₃alkyl, halo,—C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl, wherein any —C(O)C₁₋₆alkyl isoptionally substituted with —NHC(O)OC₁₋₃alkyl or —OR^(h).

In yet another aspect, R⁹ is selected from C₁₋₆alkyl, optionallysubstituted with —OR^(h) wherein R^(h) is hydrogen or C₁₋₃alkyl, andC₃₋₄cycloalkyl, optionally substituted with one or two C₁₋₃alkyl.

In a still further aspect, R⁹ is selected from cyclopropyl,2,2-dimethylcyclopropyl, tert-butyl, and 3-hydroxy-2,2-dimethylpropyl.

In a specific aspect, R¹⁰ is hydrogen, halo, or C₁₋₃alkyl, whereinC₁₋₃alkyl is optionally substituted with one, two, or three halo, orwith —OR^(d).

In a specific aspect, R¹⁰ is hydrogen, halo, or C₁₋₃alkyl substitutedwith one, two, or three halo.

In other specific aspects, R¹⁰ is hydrogen or halo; or R¹⁰ is hydrogen,chloro, or fluoro.

In another specific aspect, R¹⁰ is chloro.

In yet another specific aspect, R¹⁰ is hydrogen.

In a specific aspect, R¹¹ is selected from hydrogen, C₁₋₆alkyl, andhalo.

In another specific aspect, R¹¹ is hydrogen or C₁₋₆alkyl.

In yet another specific aspect, R¹¹ is methyl.

In a specific aspect R¹² is hydrogen.

In another specific aspect, R¹¹ and R¹² taken together form —CH₂—.

In a specific aspect, a is 0, 1, or 2.

In another specific aspect, a is 1 or 2.

In a specific aspect, b is 0, 1, or 2.

In other specific aspects, b is 1 or 2; or b is 1.

In one aspect, the invention provides compounds of formula (Ia):

wherein the variables of formula (Ia) are as defined herein.

In another aspect, the invention provides compounds of formula (Ib):

wherein the variables of formula (Ib) are as defined herein.

In yet another aspect, the invention provides compounds of formula(III):

wherein the variables of formula (III) are as defined herein.

In another aspect, the invention provides compounds of formula (IV):

wherein the variables of formula (IV) are as defined herein.

In yet another aspect, the invention provides compounds of formula (V):

wherein the variables of formula (V) are as defined herein.

In another aspect, the invention provides compounds of formula (VI):

wherein the variables of formula (VI) are as defined herein.

In another aspect, the invention provides compounds of formula (VII):

wherein the variables of formula (VII) are as defined herein.

In a further aspect, the invention provides compounds of formula (VIII):

wherein the variables of formula (VIII) are as defined herein.

In a still further aspect, the invention provides compounds of formula(IX):

wherein the variables of formula (IX) are as defined herein.

In yet another aspect, the invention provides compounds of formula (X):

wherein the variables of formula (X) are as defined herein.

In still another aspect, the invention provides compounds of formula(XI):

wherein the variables of formula (XI) are as defined herein.

In one aspect, the invention provides the compounds of Examples 1-15 andTables 1-5 below

The chemical naming convention used herein is illustrated for thecompound of Example 1:

which is[(S)-1-((S)-2-{4-[5′-chloro-4′-({6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-4-methyl-2,5-dihydro-pyrrole-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester according to the IUPAC conventions as implemented inAutoNom software, (MDL Information Systems, GmbH, Frankfurt, Germany).

The imidazole moiety in the structure of formula (I) exists intautomeric forms, illustrated below for a fragment of the compound ofExample 1

According to the IUPAC convention, these representations give rise todifferent numbering of the atoms of the imidazole moiety:{(S)-2-methyl-1-[(S)-4-methyl-2-(4-phenyl-1H-imidazol-2-yl)-2,5-dihydro-pyrrole-1-carbonyl]-propyl}-carbamicacid methyl ester (structure A) vs.{(S)-2-methyl-1-[(S)-4-methyl-2-(5-phenyl-1H-imidazol-2-yl)-2,5-dihydro-pyrrole-1-carbonyl]-propyl}-carbamicacid methyl ester (structure B).

Similarly, the napthimidazole structure of formula (II), illustrated fora fragment of the compound of Example 8, exists in tautomeric forms:

which also give rise to different numbering:{(S)-2-methyl-1-[(2S,4S)-4-methyl-2-(3H-naphtho[1,2-d]imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester (structure C) vs.{(S)-2-methyl-1-[(2S,4S)-4-methyl-2-(1H-naphtho[1,2-d]imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester (structure D). It will be understood that althoughstructures are shown, or named, in a particular form, the invention alsoincludes the tautomer thereof.

The compounds of the invention contain one or more chiral centers andtherefore, such compounds (and intermediates thereof) can exist asracemic mixtures; pure stereoisomers (i.e., enantiomers ordiastereomers); stereoisomer-enriched mixtures and the like. Chiralcompounds shown or named herein without a defined stereochemistry at achiral center are intended to include any or all possible stereoisomervariations at the undefined stereocenter unless otherwise indicated. Thedepiction or naming of a particular stereoisomer means the indicatedstereocenter has the designated stereochemistry with the understandingthat minor amounts of other stereoisomers may also be present unlessotherwise indicated, provided that the utility of the depicted or namedcompound is not eliminated by the presence of another stereoisomer.

Compounds of formula (I) also contain several basic groups (e.g., aminogroups) and therefore, such compounds can exist as the free base or invarious salt forms, such a mono-protonated salt form, a di-protonatedsalt form, a tri-protonated salt form, or mixtures thereof. All suchforms are included within the scope of this invention, unless otherwiseindicated.

This invention also includes isotopically-labeled compounds of formula(I), i.e., compounds of formula (I) where an atom has been replaced orenriched with an atom having the same atomic number but an atomic massdifferent from the atomic mass that predominates in nature. Examples ofisotopes that may be incorporated into a compound of formula (I)include, but are not limited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³⁵S, ³⁶Cl, and ¹⁸F. Of particular interest are compounds offormula (I) enriched in tritium or carbon-14, which compounds can beused, for example, in tissue distribution studies. Also of particularinterest are compounds of formula (I) enriched in deuterium especiallyat a site of metabolism, which compounds are expected to have greatermetabolic stability. Additionally of particular interest are compoundsof formula (I) enriched in a positron emitting isotope, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, which compounds can be used, for example, in PositronEmission Tomography (PET) studies.

DEFINITIONS

When describing this invention including its various aspects andembodiments, the following terms have the following meanings, unlessotherwise indicated.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched or combinations thereof. Unless otherwisedefined, such alkyl groups typically contain from 1 to 10 carbon atoms.Representative alkyl groups include, by way of example, methyl (Me),ethyl (Et), n-propyl (n-Pr) or (nPr), isopropyl (i-Pr) or (iPr), n-butyl(n-Bu) or (nBu), sec-butyl, isobutyl, tert-butyl (t-Bu) or (tBu),n-pentyl, n-hexyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl,2-ethylbutyl, 2,2-dimethylpentyl, 2-propylpentyl, and the like

When a specific number of carbon atoms are intended for a particularterm, the number of carbon atoms is shown preceding the term. Forexample, the term “C₁₋₃alkyl” means an alkyl group having from 1 to 3carbon atoms wherein the carbon atoms are in any chemically-acceptableconfiguration, including linear or branched configurations.

The term “alkoxy” means the monovalent group —O-alkyl, where alkyl isdefined as above. Representative alkoxy groups include, by way ofexample, methoxy, ethoxy, propoxy, butoxy, and the like.

The term “cycloalkyl” means a monovalent saturated carbocyclic groupwhich may be monocyclic or multicyclic. Unless otherwise defined, suchcycloalkyl groups typically contain from 3 to 10 carbon atoms.Representative cycloalkyl groups include, by way of example, cyclopropyl(cPr), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,adamantyl, and the like.

The term “heterocycle”, “heterocyclic”, or “heterocyclic ring” means amonovalent saturated or partially unsaturated cyclic non-aromatic group,having from 3 to 10 total ring atoms, wherein the ring contains from 2to 9 carbon ring atoms and from 1 to 4 ring heteroatoms selected fromnitrogen, oxygen, and sulfur. Heterocyclic groups may be monocyclic ormulticyclic (i.e., fused or bridged). Representative heterocyclic groupsinclude, by way of example, pyrrolidinyl, piperidinyl, piperazinyl,imidazolidinyl, morpholinyl, thiomorpholyl, indolin-3-yl,2-imidazolinyl, tetrahydropyranyl, 1,2,3,4-tetrahydroisoquinolin-2-yl,quinuclidinyl, 7-azanorbornanyl, nortropanyl, and the like, where thepoint of attachment is at any available carbon or nitrogen ring atom.Where the context makes the point of attachment of the heterocyclicgroup evident, such groups may alternatively be referred to as anon-valent species, i.e. pyrrolidine, piperidine, piperazine, imidazole,tetrahydropyran etc.

The term “heteroaryl” or “heteroaryl ring” means a monovalent aromaticgroup having from 5 to 10 total ring atoms, wherein the ring containsfrom 1 to 9 carbon ring atoms and from 1 to 4 ring heteroatoms selectedfrom nitrogen, oxygen, and sulfur. Heteroaryl groups may be monocyclicor multicyclic. Representative heteroaryl groups include, by way ofexample, pyrroyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl,oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,furanyl, triazinyl, thienyl, pyridyl (or, equivalently, pyridinyl),pyrimidyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, and the like, where the point ofattachment is at any available carbon or nitrogen ring atom. Where thecontext makes the point of attachment of the heteroaryl group evident,such groups may alternatively be referred to as a non-valent species,i.e. pyrrole, isoxazole, isothiazole, pyrazole, imidazole, etc.

The term “halo” means fluoro, chloro, bromo or iodo.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need of treatment.

The term “treatment” as used herein means the treatment of a disease,disorder, or medical condition in a patient (such as hepatitis C viralinfection), such as a mammal (particularly a human) which includes oneor more of the following:

(a) preventing the disease, disorder, or medical condition fromoccurring, i.e., preventing the reoccurrence of the disease or medicalcondition or prophylactic treatment of a patient that is pre-disposed tothe disease or medical condition;

(b) ameliorating the disease, disorder, or medical condition, i.e.,eliminating or causing regression of the disease, disorder, or medicalcondition in a patient, including counteracting the effects of othertherapeutic agents;

(c) suppressing the disease, disorder, or medical condition, i.e.,slowing or arresting the development of the disease, disorder, ormedical condition in a patient; or

(d) alleviating the symptoms of the disease, disorder, or medicalcondition in a patient.

The term “pharmaceutically acceptable salt” means a salt that isacceptable for administration to a patient or a mammal, such as a human(e.g., salts having acceptable mammalian safety for a given dosageregime). Representative pharmaceutically acceptable salts include saltsof acetic, ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, edisylic, fumaric, gentisic, gluconic, glucoronic,glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic,lactobionic, maleic, malic, mandelic, methanesulfonic, mucic,naphthalenesulfonic, naphthalene-1,5-disulfonic,naphthalene-2,6-disulfonic, nicotinic, nitric, orotic, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand xinafoic acid, and the like.

The term “salt thereof” means a compound formed when the hydrogen of anacid is replaced by a cation, such as a metal cation or an organiccation and the like. For example, the cation can be a protonated form ofa compound of formula (I), i.e. a form where one or more amino groupshave been protonated by an acid. Typically, the salt is apharmaceutically acceptable salt, although this is not required forsalts of intermediate compounds that are not intended for administrationto a patient.

The term “amino-protecting group” means a protecting group suitable forpreventing undesired reactions at an amino nitrogen. Representativeamino-protecting groups include, but are not limited to, formyl; acylgroups, for example alkanoyl groups, such as acetyl andtri-fluoroacetyl; alkoxycarbonyl groups, such as tert butoxycarbonyl(Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl(Bn), trityl (Tr), and 1,1-di-(4′-methoxyphenyl)methyl; silyl groups,such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS),[2-(trimethylsilyl)ethoxy]methyl (SEM); and the like. Numerousprotecting groups, and their introduction and removal, are described inT. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis,Third Edition, Wiley, New York

General Synthetic Procedures

Compounds of this invention, and intermediates thereof, can be preparedaccording to the following general methods and procedures usingcommercially-available or routinely-prepared starting materials andreagents. The substituents and variables (e.g., R¹, R², R³, R⁴, etc.)used in the following schemes have the same meanings as those definedelsewhere herein unless otherwise indicated. Additionally, compoundshaving an acidic or basic atom or functional group may be used or may beproduced as a salt unless otherwise indicated (in some cases, the use ofa salt in a particular reaction will require conversion of the salt to anon-salt form, e.g., a free base, using routine procedures beforeconducting the reaction).

Although a particular embodiment of the present invention may be shownor described in the following procedures, those skilled in the art willrecognize that other embodiments or aspects of the present invention canalso be prepared using such procedures or by using other methods,reagents, and starting materials know to those skilled in the art. Inparticular, it will be appreciated that compounds of the invention maybe prepared by a variety of process routes in which reactants arecombined in different orders to provide different intermediates en routeto producing final products.

In one exemplary method of synthesis, compounds of formula (1-7) inwhich A_(m) is defined as —NHC(O)— are prepared by a Suzuki couplingreaction in the presence of a palladium catalyst (Miyaura and Suzuki,Chem. Rev. 1995, 95, 2457-2483). As shown in Scheme 1A below, eithercoupling partner may bear the boronate moiety. Alternatively, a boronicacid reagent may be used in place of the boronate reagent, such as thepinacol boronate depicted in Scheme 1A.

and Pg represents an amino-protecting group. Protected intermediate 1-5formed by the Suzuki coupling reaction, is then deprotected, forexample, by treatment with an acid to provide compound 1-6 which isreacted with an acid chloride in the presence of base or with acarboxylic acid under amide bond formation conditions to prepare acompound of the invention of formula 1-7. When a carboxylic acid reagentHO—C(O)—R⁹ is used for the amide bond formation reaction, a couplingagent such as N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) or other coupling agents known in the art, istypically included in the reaction.

If protected intermediate 1-2 were replaced by an intermediate 1-2′

then the Suzuki coupling of the boronate 1-1 in the first step of Scheme1A would directly provide a final compound of the invention.

Another useful sequence for preparing final compounds of the inventionis illustrated in Scheme 1B:

where a protected form of the Suzuki coupling partners 1-1′ or 1-3′ inwhich the nitrogen on the ring labeled as A bears a protecting group Pg,and intermediates 1-2′ or 1-4′ bearing the substituent R⁹, are used inthe first step to form a protected intermediate 1-5′. The protectedintermediate 1-5′ is (i) deprotected conventionally, and then (ii)reacted with a reagent HO-G to provide a compound of the invention.

The bromo intermediate 1-2 may be prepared, for example, by amidecoupling of arylamine 2-1 with a fluoropyridine carbonyl chloride 2-2,followed by reaction with a protected piperazine 2-4 as shown in Scheme2.

Alternatively, intermediate 1-2 may be prepared by the reaction ofarylamine 2-1 with the carboxylic acid intermediate 3-1 as given inScheme 3.

It will be readily understood that intermediates bearing the substituentR⁹ may be prepared from the corresponding protected compound. Forexample, the bromo intermediate 1-2′, may be prepared by deprotectingintermediate 1-2 and then reacting with an acid chloride or carboxylicacid as in Scheme 1A.

A process for the preparation of intermediate 3-1 is given in thefollowing scheme.

The reaction in Scheme 4 of a fluoronicotinic acid 4-1 with theprotected piperazine 2-4 to provide intermediate 3-1 is typicallyperformed using isopropylmagnesium chloride at a temperature below about−20° C.

Intermediates 1-1 and 1-3 used in the Suzuki reaction of Scheme 1 may beprepared, for example, as shown in Schemes 5 and 6.

Reagent 5-1, where X represents bromo or chloro, is reacted with aprotected proline or piperidine carboxylic acid 5-2 to provideintermediate 5-3 which is converted to intermediate 5-4 in the presenceof an excess of ammonium acetate. The ring closure reaction typically isperformed at a temperature between about 100° C. and about 120° C. for aperiod of about 4 to about 24 hours. To provide compound 1-3,intermediate 5-4 is typically deprotected and coupled with a reagentHO-G to provide compound 1-3.

Finally, to provide boronate intermediate 1-1, intermediate 1-3 isreacted with the di-boronate 6-1 in the presence of a palladium catalystas shown in Scheme 6.

Compounds of Formula 7-5 in which the variable A_(m) is defined as—C(O)NH— are prepared by processes analogous to those described above.One exemplary process for the preparation of compounds of Formula 7-5 isshown in Scheme 7.

The acid 7-1 and aminopyridine 7-2 are reacted under amide bondformation conditions to provides a protected intermediate of formula 7-3which is then deprotected and reacted with an acid chloride orcarboxylic acid as in Scheme 1 to provide final compounds of theinvention.

The intermediates of Scheme 7 may be prepared by conventional syntheticreactions. For example, the bi-phenyl acid 7-1 may be prepared by theSuzuki coupling reaction of boronate intermediate 1-1 with abromo-benzoic acid ester followed by hydrolysis to the acid (not shown)to provide the bi-phenyl acid 7-1.

Alternatively, compounds of formula 7-5 may be prepared by the Suzukicoupling of boronate intermediate 1-1 with a bromo intermediateanalogous to intermediate 1-2 of Scheme 1.

Compounds of formula (II) may be prepared by analogous reactions usingnapthimidazole bromide or boronate reagents

in place of intermediates 1-1 and 1-3 in, for example Scheme 1 andScheme 8 and following reactions.

Details regarding specific reaction conditions and other procedures forpreparing representative compounds of the invention or intermediatesthereto are described in the examples below.

Thus, in one of its method aspects, the invention provides the processesof the schemes and variations thereto described above as well as theprocesses exemplified below.

It will further be understood, this disclosure encompasses compounds offormula (I) when prepared by synthetic processes such as those describedabove and below or by metabolic processes including those occurring invivo in human or animal body or in vitro.

Pharmaceutical Compositions

The compounds of the invention and pharmaceutically-acceptable saltsthereof are typically used in the form of a pharmaceutical compositionor formulation. Such pharmaceutical compositions may be administered toa patient by any acceptable route of administration including, but notlimited to, oral, rectal, vaginal, nasal, inhaled, topical (includingtransdermal) and parenteral modes of administration.

Accordingly, in one of its compositions aspects, the invention isdirected to a pharmaceutical composition comprising apharmaceutically-acceptable carrier or excipient and a compound offormula (I), where, as defined above, “compound of formula (I)” means acompound of formula (I) or a pharmaceutically-acceptable salt thereof.Optionally, such pharmaceutical compositions may contain othertherapeutic and/or formulating agents if desired. When discussingcompositions and uses thereof, the “compound of the invention” may alsobe referred to herein as the “active agent”. As used herein, the term“compound of the invention” is intended to include all compoundsencompassed by formulas (I) and (II) as well as the species embodied informulas (III), through (XI) and pharmaceutically-acceptable saltsthereof.

The pharmaceutical compositions of the invention typically contain atherapeutically effective amount of a compound of the present invention.Those skilled in the art will recognize, however, that a pharmaceuticalcomposition may contain more than a therapeutically effective amount,i.e., bulk compositions, or less than a therapeutically effectiveamount, i.e., individual unit doses designed for multiple administrationto achieve a therapeutically effective amount.

Typically, such pharmaceutical compositions will contain from about 0.1to about 95% by weight of the active agent; preferably, from about 5 toabout 70% by weight; and more preferably from about 10 to about 60% byweight of the active agent.

Any conventional carrier or excipient may be used in the pharmaceuticalcompositions of the invention. The choice of a particular carrier orexcipient, or combinations of carriers or excipients, will depend on themode of administration being used to treat a particular patient or typeof medical condition or disease state. In this regard, the preparationof a suitable pharmaceutical composition for a particular mode ofadministration is well within the scope of those skilled in thepharmaceutical arts. Additionally, the carriers or excipients used inthe pharmaceutical compositions of this invention arecommercially-available. By way of further illustration, conventionalformulation techniques are described in Remington: The Science andPractice of Pharmacy, 20th Edition, Lippincott Williams & White,Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems, 7th Edition, Lippincott Williams &White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, such as microcrystalline cellulose,and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients, such as cocoa butter and suppository waxes; oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols, such as propylene glycol; polyols,such as glycerin, sorbitol, mannitol and polyethylene glycol; esters,such as ethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; and other non-toxic compatible substances employed inpharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly andintimately mixing or blending the active agent with apharmaceutically-acceptable carrier and one or more optionalingredients. The resulting uniformly blended mixture can then be shapedor loaded into tablets, capsules, pills and the like using conventionalprocedures and equipment.

The pharmaceutical compositions of the invention are preferably packagedin a unit dosage form. The term “unit dosage form” refers to aphysically discrete unit suitable for dosing a patient, i.e., each unitcontaining a predetermined quantity of active agent calculated toproduce the desired therapeutic effect either alone or in combinationwith one or more additional units. For example, such unit dosage formsmay be capsules, tablets, pills, and the like, or unit packages suitablefor parenteral administration.

In one embodiment, the pharmaceutical compositions of the invention aresuitable for oral administration. Suitable pharmaceutical compositionsfor oral administration may be in the form of capsules, tablets, pills,lozenges, cachets, dragees, powders, granules; or as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-water orwater-in-oil liquid emulsion; or as an elixir or syrup; and the like;each containing a predetermined amount of a compound of the presentinvention as an active ingredient.

When intended for oral administration in a solid dosage form (i.e., ascapsules, tablets, pills and the like), the pharmaceutical compositionsof the invention will typically comprise the active agent and one ormore pharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate. Optionally or alternatively, such solid dosageforms may also comprise: fillers or extenders, such as starches,microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/orsilicic acid; binders, such as carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, suchas glycerol; disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and/or sodium carbonate; solution retarding agents, such as paraffin;absorption accelerators, such as quaternary ammonium compounds; wettingagents, such as cetyl alcohol and/or glycerol monostearate; absorbents,such as kaolin and/or bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants can also be presentin the pharmaceutical compositions of the invention. Examples ofpharmaceutically-acceptable antioxidants include: water-solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodiumbisulfate, sodium metabisulfate, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate,alpha-tocopherol, and the like; and metal-chelating agents, such ascitric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid,phosphoric acid, and the like. Coating agents for tablets, capsules,pills and like, include those used for enteric coatings, such ascellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acidmethacrylic acid estercopolymers, cellulose acetate trimellitate, carboxymethyl ethylcellulose, hydroxypropyl methyl cellulose acetate succinate, and thelike.

Pharmaceutical compositions of the invention may also be formulated toprovide slow or controlled release of the active agent using, by way ofexample, hydroxypropyl methyl cellulose in varying proportions; or otherpolymer matrices, liposomes and/or microspheres. In addition, thepharmaceutical compositions of the invention may optionally containopacifying agents and may be formulated so that they release the activeingredient only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active agent can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically-acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Liquid dosage formstypically comprise the active agent and an inert diluent, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (esp., cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Suspensions, inaddition to the active ingredient, may contain suspending agents suchas, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

The compounds of this invention can also be administered parenterally(e.g. by intravenous, subcutaneous, intramuscular or intraperitonealinjection). For parenteral administration, the active agent is typicallyadmixed with a suitable vehicle for parenteral administration including,by way of example, sterile aqueous solutions, saline, low molecularweight alcohols such as propylene glycol, polyethylene glycol, vegetableoils, gelatin, fatty acid esters such as ethyl oleate, and the like.Parenteral formulations may also contain one or more anti-oxidants,solubilizers, stabilizers, preservatives, wetting agents, emulsifiers,buffering agents, or dispersing agents. These formulations may berendered sterile by use of a sterile injectable medium, a sterilizingagent, filtration, irradiation, or heat.

Alternatively, the pharmaceutical compositions of the invention areformulated for administration by inhalation. Suitable pharmaceuticalcompositions for administration by inhalation will typically be in theform of an aerosol or a powder. Such compositions are generallyadministered using well-known delivery devices, such as a metered-doseinhaler, a dry powder inhaler, a nebulizer or a similar delivery device.

When administered by inhalation using a pressurized container, thepharmaceutical compositions of the invention will typically comprise theactive ingredient and a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas.Additionally, the pharmaceutical composition may be in the form of acapsule or cartridge (made, for example, from gelatin) comprising acompound of the invention and a powder suitable for use in a powderinhaler. Suitable powder bases include, by way of example, lactose orstarch.

The compounds of the invention can also be administered transdermallyusing known transdermal delivery systems and excipients. For example,the active agent can be admixed with permeation enhancers, such aspropylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-onesand the like, and incorporated into a patch or similar delivery system.Additional excipients including gelling agents, emulsifiers and buffers,may be used in such transdermal compositions if desired.

The following non-limiting examples illustrate representativepharmaceutical compositions of the present invention.

Oral Solid Dosage Form

A compound of the invention is dissolved in polyethylene glycolacidified to pH≦2 with optional heating to form a solution comprising10% w/w or 40% w/w active agent. The solution is spray dried to form apowder. The resulting powder is loaded into capsules, for examplegelatin or hydroxypropyl methylcellulose capsules, to provide a unitdosage of 14 mg or 56 mg, respectively, active agent per capsule.

Oral Liquid Formulation

A compound of the invention (100 mg) is added to a mixture of ethanol (5mL), propylene glycol (10 mL), and polyethylene glycol (25 mL). Oncedissolution is achieved, acidified distilled water (q.s. to 100 mL) isadded to provide a liquid formulation at a concentration of 1 mg/mLactive agent.

Lipid Emulsion Formulation

A lipid emulsion formulation comprising a compound of the invention(10%), oleic acid (78%) polyethylene glycol (10%), and polysorbate 20(2%) w/w is formed by adding a compound of the invention to a mixture ofthe remaining ingredients.

Lipid Emulsion Formulation

A lipid emulsion formulation comprising a compound of the invention(10%) and oleic acid (90%) w/w is formed by adding a compound of theinvention to oleic acid.

Micro-Emulsion Formulation

A compound of the invention (1 g) is dissolved in a mixture of ethanol(2 mL), propylene glycol (2 mL), polyethylene glycol 400 (4 mL), andpolyethylene glycol-15-hydroxystearate (4 mL). Acidified distilled water(q.s. to 100 mL) is added to form a self-emulsifying micro-emulsionformulation.

Utility

The compounds of the invention have been shown to inhibit viralreplication in HCV replicon assays and therefore are expected to beuseful for the treatment of hepatitis C viral infections.

In one aspect, therefore, the invention provides a method of inhibitingreplication of the hepatitis C virus in a mammal (e.g., a human), themethod comprising administering to the mammal atherapeutically-effective amount of a compound of the invention or of apharmaceutical composition comprising a pharmaceutically-acceptablecarrier and a compound of the invention.

The invention further provides a method of treating hepatitis C viralinfections in a mammal (e.g., a human), the method comprisingadministering to the mammal a therapeutically-effective amount ofcompound of the invention or of a pharmaceutical composition comprisinga pharmaceutically-acceptable carrier and a compound of the invention.

The compounds of the invention may inhibit viral replication byinhibiting the function of the NS5A protein encoded by the HCV genome.In one aspect, therefore, the invention provides a method of inhibitingthe NS5A protein of HCV in a mammal, the method comprising administeringto the mammal, a compound or a composition of the invention.

When used to treat HCV infections, the compounds of the invention willtypically be administered orally in a single daily dose or in multipledoses per day, although other forms of administration may be used. Theamount of active agent administered per dose or the total amountadministered per day will typically be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compoundadministered and its relative activity, the age, weight, and response ofthe individual patient, the severity of the patient's symptoms, and thelike.

Suitable doses for treating HCV infections will range from about 1 toabout 2000 mg/day of active agent, including from about 5 to about 300mg/day and from about 10 to about 200 mg per day of active agent for anaverage 70 kg human.

Combination Therapy

Compounds of the invention may also be used in combination with one ormore agents which act by the same mechanism or by different mechanismsto effect treatment of HCV. Useful classes of agents for combinationtherapy include, but are not limited to, HCV NS3 protease inhibitors,HCV NS5B nucleoside and non-nucleoside polymerase inhibitors, helicaseinhibitors, NS4B protein inhibitors, HCV viral entry inhibitors,cyclophyllin inhibitors, toll-like receptor agonists, inhibitors of heatshock proteins, interfering RNA, antisense RNA, HCV internal ribosomeentry site (IRES) inhibitors, thiazolides, nucleoside analogs such asribavirin and related compounds, interferons and other immunomodulatoryagents, inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors, andother NS5A protein inhibitors. Agents which act to inhibit HCVreplication by any other mechanism may also be used in combination withthe present compounds.

HCV NS3 protease inhibitors which may be used in combination therapyinclude, but are not limited to, Incivek® (telaprevir, VX-950),boceprevir (SCH-503034), simeprevir (TMC-435), narlaprevir (SCH-900518),vaniprevir (MK-7009), danoprevir (ITMN-191, R-7227), BI-201335,ABT-450/r, asunaprevir (BMS-650032), GS-9256, GS-9451, sovaprevir(ACH-1625), ACH-2684, BMS-605339, VX-985, PHX-1766, BMS-791325, IDX-320,and MK-5172.

Examples of HCV NS5B nucleoside polymerase inhibitors include, but arenot limited to, mericitabine (RG7128), IDX-184, sofosbuvir (GS-7977,PSI-7977), PSI-7851, PSI-938, BMS-986094 (INX-189, INX-08189), RG7348,MK-0608, TMC-649128, HCV-796, and ALS-2200 (VX-135), while,non-nucleoside HCV NS5B polymerase inhibitors, include but are notlimited to, filibuvir (PF-8685540), tegobuvir (GS-9190), VX-222, VX-759,setrobuvir (ANA-598), ABT-072, ABT-333, BI-207127, BMS-791325, MK-3281,IDX-37, BMS-824393, TMC-647055.

A wide variety of interferons and pegylated interferons, includingalpha, beta, omega, and gamma interferons, having antiviral,antiproliferative or immunomodulatory effects, can be combined with thepresent compounds. Representative examples include, but are not limitedto, Intron® A (interferon-alpha2b), Actimmune® (interferon-gamma-1b),Alferon N, Advaferon®, Roferon-A (interferon alpha-2a) PegIntron®(peginterferon-alpha 2b), Alfaferone, Pegasys® (peginterferon alpha-2a),Alfanative (interferon alpha), Zalbin™ (albinterferon alpha-2b),Infergon® (interferon alfacon-1), Omega DUROS® (omega interferon),Locteron™ (interferon alpha), PEG-rIL-29 (pegylated interferon lambda),and Rebif® (interferon beta-1a).

Nucleoside analog antiviral agents include, but are not limited to,ribavirin (Copegus®, Rebetol®, Virazole®) and Viramidine (taribavirin).Interferons and ribavirin are also provided in the form of kits whichinclude, for example, but are not limited to, Rebetron® (interferonalpha-2b/ribavirin) and Pegetron® (Peginterferon alpha-2b/ribavirin)

Useful compounds acting by other mechanisms include, but are not limitedto: cyclophilin inhibitors, such as DEB-025, SCY-635, NIM-811, andcyclosporine and derivatives; toll-like receptor agonists, such asresiquimod, IMO-2125, and ANA-773, HCV viral entry inhibitors, such ascivacir, thiazolides, such as nitazoxanide, and broad-spectrum viralinhibitors, such as, inosine-5′-monophosphate dehydrogenase (IMPDH)inhibitors.

In addition, compounds of the invention may be combined with an NS5Ainhibitor, for example, daclatasvir (BMS-790052), AZD-7295, PPI-461,PPI-1301, GS-5885, GSK2336805, ABT-267, ACH-2928, ACH-3102, EDP-239,IDX-719, MK-8742, or PPI-668.

In another aspect, therefore, the invention provides a therapeuticcombination for use in the treatment of hepatitis C viral infections,the combination comprising a compound of the invention and one or moreother therapeutic agents useful for treating HCV. For example, theinvention provides a combination comprising a compound of the inventionand one or more agents selected from HCV NS3 protease inhibitors, HCVNS5B nucleoside and non-nucleoside polymerase inhibitors, interferonsand pegylated interferons, cyclophilin inhibitors, HCV NS5A inhibitors,and ribavirin and related nucleoside analogs. Also provided, therefore,is a pharmaceutical composition comprising a compound of the inventionand one or more other therapeutic agents useful for treating HCV.

Further, in a method aspect, the invention provides a method of treatinga hepatitis C viral infection in a mammal, the method comprisingadministering to the mammal a compound of the invention and one or moreother therapeutic agents useful for treating HCV.

In another method aspect, the invention provides a method of inhibitingreplication of the hepatitis C virus in a mammal, the method comprisingadministering to the mammal a compound of the invention and one or moreother therapeutic agents useful for inhibiting replication of thehepatitis C virus.

For example, in one method aspect, the invention provides a method oftreating a hepatitis C viral infection in a mammal, the methodcomprising administering to the mammal a compound of the invention, aninterferon or pegylated interferon, and ribavirin.

In another exemplary method aspect, the invention provides a method oftreating a hepatitis C viral infection in a mammal, the methodcomprising administering to the mammal a compound of the invention, aninterferon or pegylated interferon, ribavirin, and an HCV NS3 proteaseinhibitor.

In still another method aspect, the invention provides a method oftreating a hepatitis C viral infection in a mammal, the methodcomprising administering to the mammal a compound of the invention, anHCV NS3 protease inhibitor, and ribavirin.

Still other all-oral combination therapies useful in other methodaspects, include, for example, a compound of the invention and an HCVNS3 protease inhibitor; a compound of the invention and an HCV NS5Bnucleoside polymerase inhibitor; a compound of the invention, an HCVNS5B nucleoside polymerase inhibitor, and ribavirin; a compound of theinvention, an HCV NS3 protease inhibitor, and an HCV NS5B nucleosidepolymerase inhibitor; a compound of the invention, an HCV NS3 proteaseinhibitor, an HCV NS5B nucleoside polymerase inhibitor and ribavirin; acompound of the invention, an HCV NS3 protease inhibitor, and an HCVNS5B non-nucleoside polymerase inhibitor; and a compound of theinvention, an HCV NS3 protease inhibitor, an HCV NS5B non-nucleosidepolymerase inhibitor and ribavirin.

In another method aspect, the invention provides a method of inhibitingreplication of the hepatitis C virus in a mammal, using a compound ofthe invention in combination with other agents, as described above.

When used in combination therapy, the agents may be formulated in asingle pharmaceutical composition, as disclosed above, or the agents maybe provided in separate compositions that are administeredsimultaneously or at separate times, by the same or by different routesof administration. When administered separately, the agents areadministered sufficiently close in time so as to provide a desiredtherapeutic effect. Such compositions can be packaged separately or maybe packaged together as a kit. The two or more therapeutic agents in thekit may be administered by the same route of administration or bydifferent routes of administration.

Finally, the compounds of the invention may also find utility asresearch tools, for example, for discovering new HCV NS5A proteininhibitors or explicating mechanisms of HCV replication.

Compounds of the invention have been demonstrated to be potentinhibitors of HCV replication in HCV replicon assays, as described inthe following examples.

EXAMPLES

The following synthetic and biological examples are offered toillustrate the invention, and are not to be construed in any way aslimiting the scope of the invention. In the examples below, thefollowing abbreviations have the following meanings unless otherwiseindicated. Abbreviations not defined below have their generally acceptedmeanings.

-   ACN=acetonitrile-   DCM=dichloromethane-   DIPEA=N,N-diisopropylethylamine-   DMA=N,N-dimethylacetamide-   DMF=N,N-dimethylformamide-   DMP=1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one    (Dess-Martin periodinane)-   DMSO=dimethyl sulfoxide-   EDC=N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride-   EtOAc=ethyl acetate-   h=hour(s)-   HATU=N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium    hexafluorophosphate-   HCTU=2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium    hexafluorophosphate-   HOAt=1-hydroxy-7-azabenzotriazole-   min=minute(s)-   Pd(dppf)Cl₂=dichloro(1,1′-bis(diphenylphosphino)-ferrocene)dipalladium(II)-   Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0)-   MTBE=methyl tert-butyl ether-   RT=room temperature-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   bis(pinacolato)diboron=4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]

Reagents and solvents were purchased from commercial suppliers (Aldrich,Fluka, Sigma, etc.), and used without further purification. Reactionswere run under nitrogen atmosphere, unless noted otherwise. Progress ofreaction mixtures was monitored by thin layer chromatography (TLC),analytical high performance liquid chromatography (anal. HPLC), and massspectrometry. Reaction mixtures were worked up as described specificallyin each reaction; commonly they were purified by extraction and otherpurification methods such as temperature-, and solvent-dependentcrystallization, and precipitation. In addition, reaction mixtures wereroutinely purified by preparative HPLC, typically using C18 or BDScolumn packings and conventional eluents. Typical preparative HPLCconditions are described below.

Characterization of reaction products was routinely carried out by massand ¹H-NMR spectrometry. For NMR analysis, samples were dissolved indeuterated solvent (such as CD₃OD, CDCl₃, or d₆-DMSO), and ¹H-NMRspectra were acquired with a Varian Gemini 2000 instrument (400 MHz)under standard observation conditions. Mass spectrometric identificationof compounds was performed by an electrospray ionization method (ESMS)with an Applied Biosystems (Foster City, Calif.) model API 150 EXinstrument or an Agilent (Palo Alto, Calif.) model 1200 LC/MSDinstrument.

General Preparative HPLC Conditions

Column: C18, 5 μm. 21.2×150 mm or C18, 5 μm 21×250 or C14 21×150

Column temperature: Room Temperature

Flow rate: 20.0 mL/min

Mobile Phases:

-   -   A=Water+0.05% TFA    -   B=ACN+0.05% TFA,        Injection volume: (100-1500 μL)        Detector wavelength: 214 nm

Crude compounds were dissolved in 1:1 water:acetic acid at about 50mg/mL. A 4 minute analytical scale test run was carried out using a2.1×50 mm C18 column followed by a 15 or 20 minute preparative scale runusing 100 μL injection with the gradient based on the % B retention ofthe analytical scale test run. Exact gradients were sample dependent.Samples with close running impurities were checked with a 21×250 mm C18column and/or a 21×150 mm C14 column for best separation. Fractionscontaining desired product were identified by mass spectrometricanalysis.

Supercritical Fluid Chromatography (SFC) Conditions

Instrument Thar 80

Column: AD 5 μm 30×250 mm

Column temperature: 38° C.

Nozzle pressure: 100 Bar

Nozzle temperature: 60° C.

Evaporator temperature: 20° C.

Trimmer temperature 25° C.

Injection volume: (100-1500 μL)

Detector wavelength: 220 nm

Preparation 14-(4-Bromo-phenyl)-2-((S)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl)-1H-imidazole

(a) (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester

Thionyl chloride (47 g, 393 mmol) was added dropwise at 0° C. to astirred solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid (40g, 0.31 mol) in anhydrous methanol (200 mL). The reaction was allowed toproceed overnight, and concentrated to give the title intermediate (50g). ¹H NMR (400 MHz, CD₃OD) δ (ppm) 4.56 (m, 2H), 3.85 (s, 3H), 3.41 (m,1H), 3.28 (m, 1H), 2.40 (m, 1H), 2.22 (m, 1H).

(b) (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester 2-methyl ester

To a solution of the product of the previous step (1 g, 6.89 mmol) inDCM (500 mL) was added triethylamine (68.8 g) and di-tert-butyldicarbonate (74.2 g, 0.34 mmol). The mixture was stirred at RTovernight, washed with 1 M HCl (50 mL), brine, dried over Na₂SO₄,filtered and concentrated to give the title intermediate (45 g). ¹H NMR(400 MHz, CDCl₃): δ (ppm) 4.44 (m, 1H), 4.34 (m, 1H), 3.70 (s, 3H), 3.56(m, 1H), 3.43-3.53 (m, 1H), 2.25-2.30 (m, 2H), 2.03 (m, 1H), 1.35-1.44(m, 9H).

(c) (S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester

To a solution of the product of the previous step (45 g, 0.18 mol) inDCM (500 mL) was added portionwise pyridinium chlorochromate (77.6 g,0.36 mol). The mixture was stirred at RT overnight and filtered throughCelite®. The filtrate was concentrated and purified by columnchromatography (20% EtOAc in petroleum ether) to give the titleintermediate (20 g, 46% yield). ¹H NMR (400 MHz, CDCl₃): δ (ppm) 4.72(m, 1H), 3.87-3.90 (m, 2H), 3.73 (s, 3H), 2.88-2.99 (m, 1H), 2.56 (m,1H), 1.42 (s, 9H).

(d)(S)-4-Trifluoromethanesulfonyloxy-2,5-dihydro-pyrrole-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester

To a stirred solution of 1 M sodium hexamethyldisilazane (41.1 mL, 41.10mmol) was added a stirred solution of the product of the previous step(10 g, 41.10 mmol) in dry THF (80 mL) at −78° C. under N₂. The reactionmixture was stirred at −78° C. for 30 min and then a solution ofN-phenyl-bis(trifluoromethanesulfonimide) (15.4 g, 43.16 mmol) in THF(100 mL) was added dropwise and the mixture stirred for another 2 h. Thereaction was quenched with NaHCO₃ (aq) and extracted with EtOAc (3×100mL). The combined organic phase was washed with brine, dried overNa₂SO₄, filtered, concentrated and purified by column chromatography (2%EtOAc in petroleum ether) to give the title intermediate (3.5 g, 23%yield). ¹H NMR (400 MHz, CDCl₃): δ (ppm) 5.73 (m, 1H), 5.00-5.07 (m,1H), 4.24-4.39 (m, 2H), 3.76 (s, 3H), 1.42-1.47 (m, 9H).

(e) (S)-4-Methyl-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butylester 2-methyl ester

To a solution of the product of the previous step (3.5 g, 9.33 mmol) indioxane (50 mL) was added methylboronic acid (1.12 g, 18.66 mmol),Na₂CO₃ (9.33 mL, 18.66 mmol, 2 M) and Pd(PPh₃)₄ (1.08 g, 0.93 mmol). Thereaction mixture was heated at reflux for 2 h under nitrogen, cooled toRT, filtered, and the filtrate was concentrated and purified by columnchromatography (2% EtOAc in petroleum ether) to give the titleintermediate (1.4 g, 62% yield). ¹H NMR (400 MHz, CDCl₃): δ (ppm)5.28-5.35 (m, 1H), 4.86-4.88 (m, 1H), 4.02-4.15 (m, 2H), 3.71 (s, 3H),1.76 (s, 3H), 1.40-1.46 (m, 9H).

(f) (S)-4-Methyl-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butylester

To a solution of the product of the previous step (1.4 g, 5.80 mmol) in2:1 THF:water (30 mL) was added aq. lithium hydroxide (730 mg, 17.4mmol). The mixture was stirred at RT overnight under nitrogen, adjustedto pH 2 with 1 N HCl, and extracted with EtOAc (3×50 mL). The combinedorganic phase was washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the title intermediate (1.3 g)

(g) (S)-4-Methyl-2,5-dihydro-pyrrole-1,2-dicarboxylic acid2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester

To a solution of the product of the previous step (1.3 g, 5.72 mmol) inACN (30 mL) was added diethylamine (2.22 g, 17.16 mmol) and2-bromo-1-(4-bromo-phenyl)-ethanone (2.38 g, 8.58 mmol). The reactionmixture was stirred at RT for 2 h, and diluted with 1:1 EtOAc:water (100mL). The organic layer was dried over Na₂SO₄, filtered and concentratedto give the title intermediate (2.4 g).

(h)(S)-2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-methyl-2,5-dihydro-pyrrole-1-carboxylicacid tert-butyl ester

To a solution of the product of the previous step (2.4 g, 5.66 mmol) intoluene (40 mL) was added ammonium acetate (8.72 g, 112 mmol). Thereaction mixture was heated at reflux overnight under nitrogen,concentrated, and the residue was dissolved in EtOAc (50 mL) and H₂O (50mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combinedorganic fractions were dried over Na₂SO₄, filtered, concentrated andpurified by column chromatography (10%-50% EtOAc in petroleum ether) togive the title intermediate (1.4 g, 61% yield). (m/z): [M+H]⁺ calcd forC₁₉H₂₂BrN₃O₂ 404.09, 406.09 found 404.1, 406.1.

(i)4-(4-Bromo-phenyl)-2-((S)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl)-1H-imidazole

To a cooled (0° C.) solution of the product of the previous step (1.4 g,3.46 mmol) in DCM (10 mL) was added HCl/dioxane (10 mL). The mixture wasstirred at RT for 3 h. The mixture was concentrated to give the titleintermediate (1 g). m/z): [M+H]⁺ calcd for C₁₄H₁₄BrN₃ 304.04, 306.04found 304.0, 306.0.

Preparation 2 (S)-2-Methoxycarbonylamino-3-methyl-butyric acid

Methylchloroformate (14.5 mL, 0.188 mol) was added over 15 min to acooled (0-6° C.) mixture of (S)-2-amino-3-methyl-butyric acid (20.0 g,0.171 mol), NaOH (6.80 g, 0.171 mol) and sodium carbonate (18.1 g, 0.171mol) in water (200 mL). The cooling bath was removed and the mixture wasstirred at ambient temperature overnight. Conc. aqueous HCl (30 mL) wasadded to the reaction mixture to adjust pH to ˜1. A solid formed and themixture was stirred for 90 min. The mixture was filtered and the solidwas dried overnight under reduced pressure at 40° C. t to provide thetitle intermediate (27.8 g, 93% yield). ¹H NMR (CD₃OD, 400 MHz) δ (ppm)4.87 (br. s, 2H), 4.05 (d, J=5.49, 1H), 3.65 (s, 3H), 2.25-2.05 (m, 1H),0.98 (d, J=6.87, 3H), 0.94 (d, J=6.87, 3H).

Preparation 3((S)-1-{(S)-2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-methyl-2,5-dihydro-pyrrole-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of4-(4-bromo-phenyl)-2-((S)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl)-1H-imidazole(1.10 g, 3.62 mmol) in DCM (50 mL) was added DIPEA (2.34 g, 18.1 mmol),(S)-2-methoxycarbonylamino-3-methyl-butyric acid (761 mg, 4.34 mmol) andHATU (1.65 g, 4.34 mmol). The mixture was stirred at RT overnight,washed with water (50 mL) and brine (50 mL), dried over Na₂SO₄,filtered, concentrated and purified by column chromatography (10%-50%EtOAc in petroleum ether) to give the desired product, which waspurified by supercritical fluid chromatography (SFC) [mobile phase A:supercritical CO₂, phase B: methanol+0.05% diethylamine; flow rate: 80mL/min] to give the title intermediate (750 mg, 45% yield). m/z): [M+H]⁺calcd for C₂₁H₂₅BrN₄O₃ 461.11, 463.11 found 461.1.

Preparation 4[(S)-2-Methyl-1-((S)-4-methyl-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2,5-dihydro-pyrrole-1-carbonyl)-propyl]-carbamicacid methyl ester

To a solution of((S)-1-{(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-methyl-2,5-dihydro-pyrrole-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (520 mg, 1.13 mmol) in dioxane (20 mL) was addedbis(pinacolato)diboron (430 mg, 1.69 mmol), potassium acetate (222 mg,2.26 mmol) and Pd(dppf)Cl₂ (92 mg, 0.113 mmol). The mixture was heatedat 90° C. overnight under nitrogen, filtered, and the filtrate wasextracted with water (50 mL) and EtOAc (50 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The resulting material wascombined with the product of a separate batch prepared at the 1.62 mmolscale by the same process and purified by column chromatography (20%-50%EtOAc in petroleum ether) to give the title intermediate (750 mg, 54%yield). m/z): [M+H]⁺ calcd for C₂₇H₃₇BN₄O₅ 509.29 found 509.4. ¹H NMR(400 MHz, CD₃OD): δ (ppm) 7.70 (m, 2H), 7.62 (m, 2H), 7.31 (s, 1H), 5.79(m, 1H), 5.47 (m, 1H), 4.56 (m, 2H), 3.63 (s, 3H), 1.95 (m, 1H), 1.86(s, 3H), 1.33 (s, 9H), 0.87 (m, 6H).

Preparation 54-(4-Bromo-phenyl)-2-((S)-4-cyclopropyl-2,5-dihydro-1H-pyrrol-2-yl)-1H-imidazole

Following the process of Preparation 1 steps (e) through (i)substituting cyclopropylboronic acid for methylboronic acid inPreparation 1 step (e), the title intermediate was prepared. m/z):[M+H]⁺ calcd for C₁₆H₁₆BrN₃ 330.05, 332.05 found 330.0, 332.1.

Preparation 6((S)-1-{(S)-2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyclopropyl-2,5-dihydro-pyrrole-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of4-(4-bromo-phenyl)-2-((S)-4-cyclopropyl-2,5-dihydro-1H-pyrrol-2-yl)-1H-imidazole(1.8 g, 5.45 mmol) in DCM (30 mL) was added DIPEA (3.52 g, 27.25 mmol),(S)-2-methoxycarbonylamino-3-methyl-butyric acid (1.14 g, 6.54 mmol) andHATU (2.49 g, 6.54 mmol). The mixture was stirred at RT overnight washedwith water (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated. The resulting material was combined with the product of aseparate batch prepared at the 0.61 mmol scale by the same process andpurified by column chromatography (20%-50% EtOAc in petroleum ether) togive the desired product, which was purified by SFC separation to givethe title intermediate (800 mg, 30% yield). m/z): [M+H]⁺ calcd forC₂₃H₂₇BrN₄O₃ 487.13, 489.12 found 487.1.

Preparation 7[(S)-1-((S)-4-Cyclopropyl-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2,5-dihydro-pyrrole-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of((S)-1-{(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-cyclopropyl-2,5-dihydro-pyrrole-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (800 mg, 1.64 mmol) in dioxane (30 mL) was addedbis(pinacolato)diboron (322 mg, 3.28 mmol), potassium acetate (322 mg,3.28 mmol) and Pd(dppf)Cl₂ (134 mg, 0.164 mmol). The mixture was heatedat 90° C. overnight under nitrogen, filtered, and the filtrate wasextracted with water (50 mL) and EtOAc (50 mL). The organic layer waswashed with water and brine, dried over Na₂SO₄, filtered andconcentrated. The resulting material was combined with the product of aseparate batch prepared at the 1.03 mmol scale by the same process andpurified by column chromatography (20%-50% EtOAc in petroleum ether) togive the title intermediate (1.1 g, 77% yield). m/z): [M+H]⁺ calcd forC₂₉H₃₉BN₄O₅ 535.30 found 535.3.1H NMR (400 MHz, CD₃OD): δ (ppm) 7.73 (m,2H), 7.66 (m, 2H), 7.36 (s, 1H), 5.81 (s, 1H), 5.50 (s, 1H), 4.64 (m,2H), 4.11 (m, 1H), 3.67 (s, 3H), 1.99 (m, 1H), 1.61 (m, 1H), 1.37 (s,12H), 0.91 (m, 6H), 0.80 (m, 2H), 0.70 (m, 2H).

Preparation 8(R)-4-[5-(4-Bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

(a) 4-Bromo-2-chloro-5-trifluoromethoxy-phenylamine

To a mixture of 4-bromo-3-trifluoromethoxy-phenylamine (2.0 g, 7.8 mmol)in ACN (60 mL) was slowly added a solution of N-chlorosuccinimide (1.0g, 7.8 mmol) in ACN (40 mL). The reaction mixture was heated at 60° C.overnight and extracted with ethyl acetate/water. The organic layer wasdried over sodium sulfate and purified by flash chromatography (40 gcolumn, 100% hexanes to 10% EtOAc:hexanes) to produce the desiredproduct as an orange-ish-colored oil (1.4 g, 64% yield).

(b) N-(4-Bromo-2-chloro-5-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide

To a solution of the product of the previous step (1.2 g, 4.1 mmol) inDCM (5 mL) was slowly added a solution of 2-fluoropyridine-5-carbonylchloride (0.66 g, 4.1 mmol) in DCM (3 mL) and 20 drops of DMA wereadded. The reaction mixture was concentrated to form a yellowish solid(2 g). (m/z): [M+H]⁺ calcd for C₁₃H₆BrClF₄N₂O₂ 412.92, 414.92 found 413,415.

(c)(R)-4-[5-(4-Bromo-2-chloro-5-trifluoromethoxy-phenylcarbamol)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

To a reaction mixture of the product of the previous step (999 mg, 2.42mmol) in a mixture of N,N-diisopropylethylamine (0.84 mL, 4.83 mmol);and DMSO (0.86 mL, 12.08 mmol) was added(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (726 mg, 3.62mmol) and the reaction mixture was heated at 120° C. overnight andextracted with ethyl acetate/water. The organic layer was dried oversodium sulfate and concentrated under vacuum. The dark oil was dissolvedin a small amount of DCM and purified by silica gel chromatography (24 gcolumn, 0-40% ethyl acetate:hexanes) to produce the title intermediateas a white solid (916 mg, 64% yield). (m/z): [M+H]⁺ calcd forC₂₃H₂₅BrClF₃N₄O₄ 593.07, 595.07 found 595.4.

Preparation 9(R)-5-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine

(a)(2R,5R)-2-[(Chloromethyl-dimethyl-silanyl)-methyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine

To a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (7.0g, 38 mmol), bis(chloromethyl)dimethylsilane (6.0 g, 38 mmol) in THF(150 mL) was added n-butyl-lithium (20 mL, 50 mmol) at −65 to −75° C.dropwise. The mixture was allowed to gradually warm to RT overnight. Anammonium chloride solution at 0° C. was added and the reaction mixturewas extracted with EtOAc. The organic layer was washed with water andbrine, dried over Na₂SO₄, concentrated, and purified by silica gelchromatography (2% EtOAc in petroleum ether) to give the titleintermediate (5 g, 44% yield) as a clear oil ¹H NMR: (MeOD, 400 MHz)δ(ppm): 4.15 (m, 1H), 3.99 (m, 1H), 3.72 (m, 6H), 2.95 (m, 2H), 2.30 (m,1H), 1.45 (m, 1H), 1.08 (m, 4H), 0.75 (m, 3H), 0.26 (s, 6H).

(b) (R)-2-Amino-3-(chloromethyl-dimethyl-silanyl)-propionic acid methylester

To a solution of the product of the previous step (2.7 g, 8.8 mmol) inMeOH (20 mL) was added HCl solution (7.0 mL). The mixture was stirred atRT for 5 h and concentrated to give the title intermediate (1.3 g) as ayellow oil. (m/z): [M+H]⁺ calcd for C₇H₁₆ClNO₂Si 210.06 found 210.1.

(c) (S)-3,3-Dimethyl-[1,3]azasilolidine-5-carboxylic acid methyl ester

To a solution of the product of the previous step (1.3 g, 6.2 mmol) andsodium iodide (1.3 g, 8.8 mmol) in 1:1 DCM:THF (100 mL) was added DIPEA(3.0 g, 26 mmol) at RT and the reaction mixture was stirred at RT for 5h to provide the title intermediate. (m/z): [M+H]⁺ calcd for C₇H₁₅NO₂Si174.09 found 174.1.

(d) (S)-3,3-Dimethyl-[1,3]azasilolidine-1,5-dicarboxylic acid1-tert-butyl ester 5-methyl ester

To a solution of the product of the previous step was addeddi-tert-butyl dicarbonate (1.9 g, 8.8 mmol) at RT. The reaction mixturewas stirred at RT for overnight, washed with water and extracted withEtOAc and the organic layer was washed with water and brine, dried overNa₂SO₄, concentrated, and purified by silica gel chromatography (10:1petroleum ether:EtOAc) to give the title intermediate (2.0 g) as a clearoil.

(e) (R)-3,3-Dimethyl-[1,3]azasilolidine-1,5-dicarboxylic acid1-tert-butyl ester

A solution of the product of the previous step (2.0 g, 8.8 mmol) andLiOH.H₂O (1.6 g, 38.8 mmol) in 1:1 THF:water (50 mL) was stirred at RTovernight, acidified to pH 3-4 with 1 N HCl, and extracted with EtOAc.The organic layer was washed with water and brine, dried over Na₂SO₄ andconcentrated to give the title intermediate (1.6 g) as a clear oil.

(f) (R)-3,3-Dimethyl-[1,3]azasilolidine-1,5-dicarboxylic acid5-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester

A mixture of the product of the previous step (1.6 g, 5.7 mmol),2-bromo-1-(4-bromo-phenyl)-ethanone (1.6 g, 5.7 mmol), and potassiumcarbonate (2.4 g, 17 mmol) in DCM (100 mL) was stirred at RT for 2 h,washed with water, and extracted with EtOAc. The organic layer waswashed with water and brine, dried over Na₂SO₄, and concentrated toprovide the title intermediate (2.5 g, 53% yield) as a yellow oil.(m/z): [M+H-Boc]⁺ calcd for C₁₄H₁₈BrNO₃Si 356.02 found 356.1.

(g)(R)-5-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine-1-carboxylicacid tert-butyl ester

A mixture of the product of the previous step (2.5 g, 5.7 mmol),ammonium acetate (10 g, 0.13 mol) in toluene (100 mL) was stirred at110-130° C. overnight, washed with water, and extracted with EtOAc. Theorganic layer was washed with water and brine, dried over Na₂SO₄,concentrated, and purified by silica gel chromatography (8.5% EtOAc inpetroleum ether) to give the title intermediate (400 mg, 17% yield) as abrown oil. (m/z): [M+H-Boc]⁺ calcd for C₁₉H₂₆BrN₃O₂Si 436.10, 438.10found 438.0. ¹H NMR (MeOD, 400 MHz) δ (ppm): 7.62 (m, 2H), 7.45 (m, 2H),7.19 (s, 1H), 5.50 (m, 1H), 2.88 (m, 1H), 2.50 (m, 2H), 1.98 (m, 1H),1.45 (s, 9H), 1.26 (m, 1H), 0.26 (m, 6H).

(h)(R)-5-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine

A solution of the product of the previous step (400 mg, 0.92 mmol) inHCl/MeOH (30 mL) was stirred at RT for 2 h and concentrated to give thetitle intermediate (350 mg) as a green solid. (m/z): [M+H]⁺ calcd forC₁₄H₁₈BrN₃Si 336.05 found 336.0.

Preparation 10((S)-1-{(R)-5-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

A mixture of(R)-5-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine(350 mg, 0.92 mmol, Preparation 9),(S)-2-methoxycarbonylamino-3-methyl-butyric acid (170 mg, 0.97 mmol),HATU (400 mg, 1.05 mmol), and DIPEA (700 mg, 5.4 mmol), in DCM (50 mL)was stirred at RT overnight. The reaction mixture was washed with waterand brine, dried over Na₂SO₄, concentrated, and purified by silica gelchromatography (20% EtOAc in petroleum ether) to give the titleintermediate (300 mg, 66% yield) as a straw yellow solid. (m/z): [M+H]⁺calcd for C₂₁H₂₉BrN₄O₃Si 493.12 found 493.1.

Preparation 11[(S)-1-((R)-3,3-Dimethyl-5-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-[1,3]azasilolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methylester

A mixture of((S)-1-{(R)-5-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (300 mg, 0.60 mmol, Preparation 10),bis(pinacolato)diboron (190 mg, 0.75 mmol), and potassium acetate (200mg, 2.04 mmol), Pd(dppf)Cl₂ (30 mg, 0.04 mmol) in dioxane (100 mL) wasdegassed under vacuum and purged with nitrogen several times. Themixture was stirred at 100° C. overnight, concentrated and the crudeproduct was washed with water and extracted with EtOAc. The organiclayer was washed with water and brine, dried over Na₂SO₄, concentrated,and purified by silica gel chromatography (1:1 EtOAc:petroleum ether) togive (130 mg, 40% yield) of a mixture of the title intermediate and thecorresponding boronic acid as a yellow solid. (m/z): [M+H]⁺ calcd forC₂₇H₄₁BN₄O₅Si 541.29 found 541.3. Boronic acid: (m/z): [M+H]⁺ calcd forC₂₁H₃₁BN₄O₅Si 459.22 found 459.2.

Preparation 127-Bromo-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-3H-naphtho[1,2-d]imidazole

(a)(2S,4S)-2-(2-Amino-6-bromo-naphthalen-1-ylcarbamoyl)-4-methyl-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of 6-bromo-naphthalene-1,2-diamine (2.0 g, 8.5 mmol) inDMF (150 mL) was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (2.14 g, 10.2 mmol), DIPEA (3.29 g, 25.5 mmol),and HATU (4.84 g, 12.7 mmol). The reaction mixture was stirred at RTovernight and extracted with EtOAc/H₂O (150 mL). The organic layer wasdried over Na₂SO₄, filtered, concentrated, and purified by silica gelchromatography (2:1 EtOAc:petroleum ether) to provide the titleintermediate (1.6 g)

(b)(2S,4S)-2-(7-Bromo-3H-naphtho[1,2-d]imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylicacid tert-butyl ester

A solution of the product of the previous step (1.6 g, 3.57 mmol) inacetic acid (15 mL) was heated to 60° C. under nitrogen for 1 h,adjusted to pH 8-10 with 1 N NaOH, and extracted with DCM. The organiclayer was dried over Na₂SO₄, filtered, and concentrated to give thetitle intermediate (1.5 g). (m/z): [M+H]⁺ calcd for C₂₁H₂₄BrN₃O₂ 430.11,432.11 found 432.1.

(c)7-Bromo-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-3H-naphtho[1,2-d]imidazole

To a solution of the product of the previous step (1.5 g, 3.5 mmol) inDCM (20 mL) was added TFA (2 mL). The mixture was stirred at RT for 5 h,adjusted to pH˜10 with 1 N NaOH (5 mL) and extracted with DCM (3×200mL). The reaction mixture was dried over Na₂SO₄, filtered, andconcentrated to give the title intermediate (1.1 g). (m/z): [M+H]⁺ calcdfor C₁₆H₁₆BrN₃ 330.05, 332.05 found 330.2, 332.1.

Preparation 13((S)-2-Methyl-1-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

(a){(S)-1-[(2S,4S)-2-(7-Bromo-3H-naphtho[1,2-d]imidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

To a solution of7-bromo-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-3H-naphtho[1,2-d]imidazole(1.05 g, 3.2 mmol; Preparation 12) in DCM (20 mL) was added(S)-2-Methoxycarbonylamino-3-methyl-butyric acid (672 mg, 3.84 mmol),DIPEA (825 mg, 6.4 mmol), and HATU (1.82 g, 4.8 mmol). The reactionmixture was stirred at RT for 4 h and extracted with DCM (3×250 mL). Theorganic layer was dried over Na₂SO₄, filtered, concentrated, andpurified by silica gel chromatography (1:1 EtOAc:petroleum ether) toprovide the title intermediate (1.2 g) (m/z): [M+H]⁺ calcd forC₂₃H₂₇BrN₄O₃ 487.13, 489.12 found 489.2.

(b)((S)-2-Methyl-1-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

To a solution of the product of the previous step (1.1 g, 2.2 mmol) indioxane (20 mL) was added4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (838 mg,3.3 mmol), Pd(dppf)Cl₂ (161 mg, 0.22 mmol) and potassium acetate (646mg, 6.6 mmol) at RT under nitrogen. The reaction mixture was stirred at90° C. overnight and extracted with EtOAc/H₂O (3×150 mL). The organiclayer was dried over Na₂SO₄, filtered, concentrated, and purified bysilica gel chromatography (2:1 petroleum ether:EtOAc) to provide thetitle intermediate (450 mg). (m/z): [M+H]⁺ calcd for C₂₉H₃₉BN₄O₅ 535.30found 535.3. ¹H NMR: (DMSO-d₆, 400 MHz) δ (ppm) 0.64˜0.86 (m, 6H), 1.09(s, 3H), 1.31 (s, 12H), 1.85˜1.90 (m, 2H), 2.20˜2.38 (m, 1H), 2.51 (s,1H), 3.31˜3.33 (m, 1H), 3.51 (s, 3H), 4.01˜4.07 (m, 1H), 4.11˜4.16 (m,1H), 5.09˜5.10 (m, 1H), 7.15 (d, J=8.0 Hz, 2H), 7.60˜7.79 (m, 3H),8.23˜8.37 (m, 2H), 12.5˜13.55 (d, 1H).

Preparation 14 4-Bromo-3-trifluoromethoxy-benzoic acid methyl ester

A mixture of 4-amino-3-(trifluoromethoxy)benzoic acid (504.1 mg, 2.28mmol), methanol (7.6 mL) and 4.0 M HCl in 1,4-dioxane (5.7 mL) wasstirred at RT over the weekend, concentrated, evaporated with EtOAc(3×10 mL), and dried under vacuum to give a brownish solid. The solidwas dissolved in a mixture of acetonitrile (23 mL) and water (2.3 mL).Copper(II) bromide (595 mg, 2.66 mmol) and tert-butyl nitrite (0.39 mL,3.32 mmol) were added to the reaction mixture which was heated at 70° C.for 1.5 h, cooled to RT and diluted with EtOAc (70 mL). The organiclayer was washed with saturated sodium bicarbonate (2×15 mL), brine(2×15 mL), dried over sodium sulfate, filtered and concentrated to givea brownish oil, which was purified by silica gel chromatography (24 gsilica gel, 0-50% EtOAc/Hexanes). Desired fractions were combined andconcentrated to give the title intermediate (281 mg, 41% yield) as ayellowish oil.

Preparation 154′-{2-[(S)-4-Cyclopropyl-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-2,5-dihydro-1H-pyrrol-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylicacid

To a mixture of 4-bromo-3-trifluoromethoxy-benzoic acid methyl ester(124 mg, 0.42 mmol),[(S)-1-((S)-4-Cyclopropyl-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2,5-dihydro-pyrrole-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (200 mg, 0.37 mmol; Preparation 7) and potassiumcarbonate (233 mg, 1.68 mmol) at RT was added toluene (0.92 mL) followedby water (0.47 mL). The resulting mixture was degassed and flushed withnitrogen and Pd(dppf)Cl₂ (18.5 mg, 0.023 mmol) was added under anatmosphere of nitrogen. The reaction mixture was capped and held at 100°C. overnight, cooled to RT and partitioned between EtOAc (10 mL) andwater (2 mL). The organic layer was dried over sodium sulfate, filteredand concentrated to give a brownish oil which was dissolved in a mixtureof methanol (3.8 mL) and water (2 mL) and treated with lithium hydroxidemonohydrate (95 mg, 2.27 mmol) at 65° C. for 1 hr. The reaction mixturewas concentrated, dissolved in 1:1 acetic acid:water (6 mL), filteredand purified by reverse phase HPLC. Desired fractions were combined andfreeze dried to give the TFA salt of the title intermediate (140 mg, 51%yield) as a white solid. (m/z): [M+H]⁺ calcd for C₃₁H₃₁F₃N₄O₆ 613.22found 613.6.

Preparation 16(R)-4-(5-Carboxy-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acidtert-butyl ester

A mixture of 6-fluoronicotinic acid (150 g, 1.063 mol) and(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (234.2 g,1.169 mol) in tetrahydrofuran (1.75 L) was cooled to −40° C. and then 2M isopropylmagnesium chloride in tetrahydrofuran (1.196 L, 2.39 mol) wasadded slowly maintaining the temperature at less than −20° C. Thereaction mixture was slowly warmed to RT, stirred at RT for 4 h and then1 N HCl (1.75 L) and water (1.175 L) were added. The reaction mixturewas extracted with ethyl acetate (4 L). The organic phase was evaporatedto provide crude solid (534 g). To the crude solid was added acetone (2L) and water (200 mL). The resulting reaction mixture was heated to 50°C. and then water (2.8 L) was added slowly. Seed crystals from aprevious run at smaller scale were added after ˜1 L of water. Thereaction mixture was cooled to 20° C. over 3 h, stirred at 20° C.overnight and filtered. The solid was washed with 2:3 acetone:water(2×500 mL) and dried under vacuum to provide the title compound (329 g,96% yield) as an off-white solid. HPLC Method A: Retention time 9.73min.

Preparation 174-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphth[1,2-d]imidazol-7-yl}-3-trifluoromethoxy-benzoicacid

(a)4-{2-[(2S,4S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphth[1,2-d]imidazol-7-yl}-3-trifluoromethoxy-benzoicacid methyl ester

A solution of((S)-2-methyl-1-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester (250 mg, 0.48 mmol; Preparation 13),4-bromo-3-trifluoromethoxy-benzoic acid methyl ester (140 mg, 0.47mmol), and potassium carbonate (323 mg, 2.34 mmol) in toluene (2 mL) andwater (0.5 mL) was purged with nitrogen for 5 min, then Pd(dppf)Cl₂(20.5 mg, 0.029 mmol) was added. The reaction mixture was stirred at100° C. overnight, diluted with ethyl acetate (50 mL), washed with water(2×5 mL). The organic layer was dried over magnesium sulfate, filtered,concentrated, and purified by silica gel chromatography (EtOAc/hexane 20to 100%) to give the title intermediate (284 mg, 97% yield). (m/z):[M+H]⁺ calcd for C₃₂H₃₂F₃N₄O₆ 627.24 found 627.3.

(b)4-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphth[1,2-d]imidazol-7-yl}-3-trifluoromethoxy-benzoicacid

A solution of the product of the previous step in methanol (10 mL) wasstirred with lithium hydroxide (112 mg, 2.34 mmol) in water (2 mL) at65° C. for 2 h, concentrated, dissolved in 1:1 acetic acid:water (5 mL),filtered and purified by reverse phase HPLC to provide the TFA salt ofthe title intermediate (273 mg, 80% yield). (m/z): [M+H]⁺ calcd forC₃₁H₃₁F₃N₄O₆ 613.22 found 613.2.

Preparation 18 (S)-Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-aceticacid

A solution of (S)-amino-(tetrahydro-pyran-4-yl)-acetic acid (1 g, 6.28mmol) in saturated aqueous sodium bicarbonate solution (12.32 mL, 125.6mmol) was stirred until all solids were dissolved. Methyl chloroformate(0.97 mL, 12.56 mmol) was added dropwise, the reaction mixture wasstirred for 1 h, and 1N HCl was added to adjust pH to 1. The reactionmixture was extracted with ethyl acetate (3×15 mL) and the organicextracts were dried over sodium sulfate, filtered, concentrated anddried overnight under vacuum to give the title intermediate (1.36 g, 99%yield) as a white, sticky solid. (m/z): [M+H]⁺ calcd for C₉H₁₅NO₅ 218.10found 218.3.

Preparation 19 (S)-5-Methyl-piperidine-1,2-dicarboxylic acid1-tert-butyl ester

(a) (S)-6-Oxo-piperidine-2-carboxylic acid

A mixture of (S)-2-amino-hexanedioic acid (50 g, 310.25 mmol), aceticacid (100 mL), and water (400 mL) water was refluxed for 3 h. Theunchanged starting amino acid was filtered off (24 g) and the filtrateevaporated, dissolved in hot water (50 mL) and then cooled. Acrystalline precipitate formed which was filtered to provide the titleintermediate (20 g, 45% yield).

(b) (S)-6-Oxo-piperidine-2-carboxylic acid ethyl ester

To a mixture of the product of the previous step (8.4 g, 58.68 mol) indry ethanol (200 mL) was added thionyl chloride (69.81 g, 586.8 mol)slowly at 0° C. The reaction mixture was stirred at RT overnight andthen water was added and the reaction mixture was extracted with EtOAc.The organic layers were washed with sodium bicarbonate and brine, driedover Na₂SO₄, filtered, and concentrated to provide the titleintermediate (6 g). (m/z): [M+H]⁺ calcd for C₈H₁₃NO₃ 172.09 found 172.1.

(c) (S)-6-Oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester

To a mixture of(S)-6-oxo-piperidine-2-carboxylic acid ethyl ester (12 g,70.10 mmol) in dry ACN (100 mL) was added 4-dimethylaminopyridine (25.69g, 210.30 mmol) slowly and followed by di-tert-butyl dicarbonate (30.6g, 140.20 mmol) dropwise at 0° C. The reaction mixture was stirred at RTovernight, and filtered. The organic layer was concentrated and purifiedby silica gel chromatography (3:1 petroleum ether:EtOAc) to provide thetitle intermediate (13 g, 68% yield). ¹H NMR (400 MHz, CDCl₃): δ (ppm)4.70-4.60 (m, 1H), 4.26-4.17 (m, 2H), 2.63-2.53 (m, 1H), 2.51-2.45 (m,1H), 2.20-2.12 (m, 1H), 2.08-1.96 (m, 1H), 1.80-1.70 (m, 2H), 1.50 (s,9H), 1.30-1.25 (m, 3H).

(d) (S)-5-Methyl-6-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester

To the product of the previous step (5 g, 18.43 mmol) in dry toluene(100 mL) was added 1 M lithium bis(trimethylsilyl)amide (21 mL) in THF(21 mmol) at −78° C. After 1 h, methyl trifluoromethane sulfonate (3.63g, 22.11 mmol) was added dropwise and the reaction mixture was stirredat −78° C. for 2.5 h. Saturated aqueous ammonium chloride was added andallowed to warm to RT. The organic layer was separated and the aqueouslayer was extracted with EtOAc. The combined organic layer was washedwith water and brine, and dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatography(eluting with 1:3 EtOAc:petroleum ether) to give the title intermediate(3.8 g, 72% yield). (m/z): [M-Boc+H]⁺ calcd for C₁₄H₂₃NO₅ 186.16 found186.1.

(e) (S)-5-Methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester

To a solution of (S)-5-methyl-6-oxo-piperidine-1,2-dicarboxylic acid1-tert-butyl ester 2-ethyl ester (10 g, 35 mmol) in THF (150 mL) wasadded borane dimethylsulfide complex (49 mL, 49 mmol). The reactionmixture was stirred at 0° C. for 1 h, and then stirred at 40° C. for 3h. Methanol was added and the reaction mixture was concentrated, washedwith 1 M HCl, and extracted with EtOAc/water to give the oil layer,which was dried, and concentrated. The crude product was purified bysilica gel chromatography (20:1 petroleum ether:EtOAc) to provide thetitle intermediate (2 g, 21% yield). (m/z): [M-100+H]⁺ calcd forC₁₄H₂₅NO₄ 172.18 found 172.2.

(f) (S)-5-Methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester

To a solution of (S)-5-methyl-piperidine-1,2-dicarboxylic acid1-tert-butyl ester 2-ethyl ester (1.4 g, 5.16 mmol) in methanol (15 mL)and water (5 mL) was added lithium hydroxide monohydrate (650 mg, 15.48mmol). The reaction mixture was stirred at RT overnight and concentratedto give the residue, which was extracted with EtOAc/water. The aqueouslayer was acidified with 1 N HCl, and extracted with EtOAc to give theorganic layer, which was dried and concentrated to give the crudeproduct.

Preparation 20((S)-1-{(2S,5S)-2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a) (S)-5-Methyl-piperidine-1,2-dicarboxylic acid2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester

To a mixture of (S)-5-methyl-piperidine-1,2-dicarboxylic acid1-tert-butyl ester (1.8 g, 7.4 mmol) and2-bromo-1-(4-bromophenyl)ethanone (2.47 g, 8.88 mmol) in acetonitrile(50 mL) was added DIPEA (2.87 g, 22.19 mmol). The reaction mixture wasstirred at RT overnight, concentrated, purified by silica gelchromatography (3:1 petroleum ether:EtOAc) to provide the titleintermediate (1.5 g). (m/z): [M+H-Boc]⁺ calcd for C₂₀H₂₆BrNO₅ 340.10,342.10. found 340.1, 342.1.

(b)(2S,5S)-2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine-1-carboxylicacid tert-butyl ester

A mixture of (S)-5-methyl-piperidine-1,2-dicarboxylic acid2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester (2.4 g, 5.45mmol) and ammonium acetate (8.4 g, 109 mmol) in toluene (60 mL) wasrefluxed overnight. The reaction mixture was extracted with EtOAc/waterto give the oil layer, which was dried, concentrated and purified bysilica gel chromatography (1:1 petroleum ether:EtOAc) to provide theproduct (1.3 g) which was purified by supercritical fluid chromatography(SFC) [mobile phase A: supercritical CO₂, phase B: ethanol+0.05% NH₄OH;A:B 70:30; flow rate 60 mL/min] to provide the title intermediate (0.4g, 20% yield) and trans isomer (0.26 g). ¹H NMR (400 MHz, (CD₃)₂CO): δ(ppm) (d, 3H, J=2.4 Hz), 1.44 (s, 9H), 1.50-1.60 (m, 2H), 1.70-1.90 (m,1H), 1.28 (s, 4H), 2.40-2.70 (m, 2H), 3.70-4.18 (m, 1H), 5.44 (s, 1 h),7.47 (d, J=2 Hz, 2H), 7.53 (m, 1H), 7.77 (d, 2H, J=2 Hz)

(c) (2S,5S)-2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine

A mixture of the product of the previous step (400 mg, 0.95 mmol) and 4M HCl in dioxane (10 mL) was stirred at RT for 3 h and concentrated togive the title intermediate (300 mg).

(d)((S)-1-{(2S,5S)-2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

A mixture of(2S,5S)-2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine (400mg, 1.25 mmol) and (S)-2-methoxycarbonylamino-3-methyl-butyric acid (219mg, 1.25 mmol), HATU (475 mg, 1.25 mmol), and DIPEA (485 mg, 3.75 mmol)in DCM (20 mL) was stirred at RT overnight. The reaction mixture wasconcentrated and purified by thin layer chromatography (1:1 petroleumether:EtOAc) to provide the title intermediate (550 mg, 92% yield).(m/z): [M+H]⁺ calcd for C₂₂H₂₈BrN₄O₃ 476.13, 478.13. found 478.7.

Preparation 21[(S)-2-Methyl-1-((2S,5S)-5-methyl-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-piperidine-1-carbonyl)-propyl]-carbamicacid methyl ester

A mixture of((S)-1-{(2S,5S)-2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (850 mg, 1.78 mmol) and bis(pinacolato)diboron (452mg, 1.78 mmol), potassium acetate (350 mg, 3.56 mmol), and Pd(dppf)Cl₂(170 mg) in dioxane (20 mL) was stirred at reflux for 3 h. The reactionmixture was concentrated and purified by silica gel chromatography (1:1petroleum ether:EtOAc) to provide the title intermediate (220 mg, 24%yield). (m/z): [M+H]⁺ calcd for C₂₈H₄₀BN₄O₅ 524.31. found 525. ¹H NMR(400 MHz, CDCl₃: δ (ppm) 0.70-090 (m, 4H), 0.97-1.03 (m, 5H), 1.28 (s,4H), 1.30-1.60 (m, 2H), 1.80-2.10 (m, 3H), 2.74 (m, 1H), 3.60 (s, 1H),3.61 (s, 2H), 4.20 (d, 1H, J=8.4 Hz), 4.50 (d, J=12.8 Hz, 1H), 5.53 (s,1H), 7.45-7.57 (m, 2H), 7.60-7.78 (m, 3H).

Preparation 22(1R,3S,4S)-3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

(a)(1S,3S,4R)-2-((R)-1-Phenyl-ethyl)-2-aza-bicyclo[2.2.1]hept-5-ene-3-carboxylicacid ethyl ester

To a solution of (R)-1-phenyl-ethylamine (59 g, 0.49 mmol) dissolved intoluene (500 mL) was added sodium sulfate (173 g, 1.22 mmol) followed byoxo-acetic acid ethyl ester (134 g, 0.49 mmol, 50% in toluene) dropwise.The reaction mixture was stirred at RT for 1 h. The solid was filteredand the filtrate was concentrated under vacuum to provide((R)-1-phenyl-ethylimino)-acetic acid ethyl ester, which was dissolvedin DMF (300 mL) at RT. TFA (56 g, 0.49 mmol) was added dropwise at RT,followed after 10 min by cyclopenta-1,3-diene (65 g, 0.98 mmol) andwater (0.25 ml). The mixture was stirred at RT overnight, concentratedunder vacuum and the residue was poured into a 10% aqueous solution ofNaHCO₃ (500 mL). The solution was adjusted to pH 8 with solid Na₂CO₃,and extracted with EtOAc (3×80 mL). The combined organic layers werepurified by silica gel chromatography (30:1-15:1 petroleum ether:EtOAc)to provide the title intermediate (35 g, 26% yield), as a colorless oil.(m/z): [M+H]⁺ calcd for C₁₇H₂₁NO₂ 272.16 found 272.2.

(b)(1R,3S,4S)-2-((R)-1-Phenyl-ethyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylicacid ethyl ester

A mixture of the product of the previous step (6 g, 22.11 mmol) and Pd/C(0.6 g) in EtOH (300 mL) was stirred at RT under H₂ (30 psi) overnight.The mixture was filtered and 1 mL of conc. HCl was added to thefiltrate. The solution was concentrated under vacuum to afford the titleintermediate (6 g, 100%), as white solid. (m/z): [M+H]⁺ calcd forC₁₇H₂₃NO₂ 274.17 found 274.2.

(c) (1R,3S,4S)-2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid2-tert-butyl ester

A mixture of the product of the previous step (1 g, 3.66 mmol) andPd(OH)₂/C (100 mg, 1% H₂O) in methanol (50 mL) was stirred at 40° C.under hydrogen (50 psi) overnight, filtered and concentrated undervacuum to provide (1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-3-carboxylicacid ethyl ester (0.6 g, 100%), as pale yellow solid, which was mixedwith concentrated aqueous HCl (10 mL). The reaction mixture wasconcentrated under vacuum to provide(1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (0.5 g) as apale yellow solid.

A mixture of the pale yellow solid (0.5 g), NaOH (0.44 g, 11.01 mmol),THF (20 mL) and water (4 mL) was stirred at RT for 0.5 h and then,di-tert-butyl dicarbonate (0.8 g, 3.67 mmol) was added dropwise. Thereaction mixture was stirred at RT overnight. THF was removed underreduced pressure and water (20 mL) was added. The solution was washedwith EtOAc (2×10 mL). The aqueous layer was adjusted to pH 5 with 3 MHCl and freeze dried. The solid was dissolved in 1:8 methanol:DCM (30mL) and filtered and the filtrate was concentrated under vacuum toprovide the title intermediate (220 mg), as white solid. (m/z):[M+H-tBu]⁺ calcd for C₁₂H₁₉NO₄ 186.07 found 186.1.

(d) (1R,3S,4S)-2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid3-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 2-tert-butyl ester

A mixture of compound(1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid2-tert-butyl ester (3 g, 12.43 mmol), 2-bromo-1-(4-bromophenyl)ethanone(3.80 g, 12.43 mmol) and cesium carbonate (12.15 g, 37.30 mmol) in ACN(500 mL) was stirred at RT overnight. The reaction mixture was filteredand the solid was washed with EtOAc (3×50 mL). The filtrate wasconcentrated under vacuum and purified by silica gel chromatography(20:1-5:1 petroleum ether:EtOAc) to provide the title intermediate (3 g,45% yield) as a white solid. (m/z): [M+H-tBu]⁺ calcd for C₂₀H₂₄BrNO₅382.02, 384.02 found 381.9.

(e)(1R,3S,4S)-3-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

A mixture of the product of the previous step (3 g, 5.57 mmol) andammonium acetate (4.29 g, 55.73 mmol) in toluene (500 mL) was stirred at100° C. overnight, concentrated under vacuum, dissolved in DCM (500 mL)and washed with water (3×50 mL). The organic layer was dried withNa₂SO₄, filtered, concentrated under vacuum, and purified by silica gelchromatography (20:1-5:1 petroleum ether:EtOAc) to provide the titleintermediate (1.6 g, 69% yield) as a white solid. (m/z): [M+H]⁺ calcdfor C₂₀H₂₄BrN₃O₂ 418.11, 420.11 found 418.1.

(f)(1R,3S,4S)-3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

A mixture of the product of the previous step (1.50 g, 3.59 mmol),bis(pinacolato)diboron (1.00 g, 3.94 mmol), Pd(dppf)Cl₂ (150 mg, 10.76mmol) and potassium acetate (1.06 g, 10.76 mmol) in 1,4-dioxane (200 mL)was stirred at 80° C. for 3 h under nitrogen, concentrated under vacuum,and purified by silica gel chromatography (10:1-5:1 petroleumether:EtOAc) to provide the title intermediate (500 mg, 44% yield) as awhite solid. (m/z): [M+H]⁺ calcd for C₂₆H₃₆BN₃O₄ 466.28 found 466.4 ¹HNMR (400 MHz, CH₃OD): δ (ppm) 1.18 (s, 6H), 1.23 (s, 2H), 1.25 (s, 4H),1.34 (s, 9H), 1.36-1.41 (m, 1H), 1.58-1.65 (m, 1H), 1.65-1.78 (m, 2H),1.79-1.97 (m, 2H), 2.55-2.70 (m, 1H), 4.22-4.35 (m, 1H), 4.45 (d,J=12.57 Hz, 1H), 7.34 (d, J=12.35 Hz, 1H), 7.56-7.84 (m, 4H).

Preparation 23[(S)-2-{(2S,4S)-4-Methyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

(a)7-Bromo-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-3H-naphth[1,2-d]imidazole

A mixture of(2S,4S)-2-(7-bromo-3H-naphtho[1,2-d]imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylicacid tert-butyl ester (300 mg, 0.70 mmol) and 4 M HCl in 1,4-dioxane (2mL) was heated at 50° C. for 1 h, concentrated, dissolved in EtOAc, andevaporated with EtOAc (2×) to provide the HCl salt of the titleintermediate as a yellow solid. (m/z): [M+H]⁺ calcd for C₁₆H₁₆BrN₃330.05, 332.05 found 331.9.

(b)[(S)-2-[(2S,4S)-2-(7-Bromo-3H-naphth[1,2-c]imidazol-2-yl)-4-methyl-pyrrolidin-1-yl]-2-oxo-1-(tetrahydropyran-4-yl)-ethyl]-carbamicacid methyl ester

The yellow solid from the previous step was dissolved in DMF (5 mL) andDIPEA (0.61 mL, 3.5 mmol) was added. A solution of(S)-methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (189 mg,0.87 mmol) and HATU (331 mg, 0.871 mmol) dissolved in DMF (5 mL) wasadded. The reaction mixture stirred at RT for 1 h, dissolved in EtOAc(100 mL) and washed with water (300 mL). The aqueous layer was extractedwith EtOAc (100 mL). The combined organic layer was washed with brine,dried over sodium sulfate, filtered, concentrated, and purified bysilica gel chromatography (0-100% EtOAc:hexanes) to produce the titleintermediate (344 mg, 90% yield) as a light colored solid. (m/z): [M+H]⁺calcd for C₂₅H₂₉BrN₄O₄ 529.14, 531.14 found 529.1.

(c)[(S)-2-{(2S,4S)-4-Methyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

The product of the previous step (344 mg, 0.65 mmol),bis(pinacolato)diboron (250 mg, 0.97 mmol), and potassium acetate (96mg, 0.97 mmol) were mixed with 1,4-dioxane (2.2 mL). The resultingsuspension was sparged under nitrogen before Pd(dppf)Cl₂ CH₂Cl₂ (26 mg,0.032 mmol) was added and the reaction mixture was heated at 100° C.overnight, cooled to RT and filtered through a stacked pad of silica gelatop Celite®. The pad was washed with EtOAc (180 mL). The filtrate wasconcentrated to give a black oil, which was loaded on a 12 g gold silicagel disposable column with DCM (eluted with 0-100% EtOAc:hexanes).Desired fractions were combined and concentrated to give the titleintermediate (256 mg) as a yellowish foam. (m/z): [M+H]⁺ calcd forcorresponding boronic acid C₂₅H₃₁BN₄O₆ 495.231 found 495.0.

Preparation 24 (1R,3S,6S)-2-Aza-bicyclo[4.1.0]heptane-2,3-dicarboxylicacid 2-tert-butyl ester

(b) (S)-6-Hydroxymethyl-piperidin-2-one

To a solution of (S)-6-oxopiperidine-2-carboxylic acid (17 g, 120 mmol)in methanol (200 mL) was added thionyl chloride (87 mL, 1.2 mol) and thereaction mixture was stirred at RT overnight, concentrated, combinedwith the product of a similar preparation, washed with saturated aqueousNaHCO₃, and extracted with EtOAc (4×200 mL). The organic layers werecombined, dried over sodium sulfate and evaporated to provide crude(S)-methyl 6-oxopiperidine-2-carboxylate (36.5 g).

To a solution of the product of the previous step (18.5 g, 117.7 mmol)in ethanol (200 mL) was added sodium borohydride (6.7 g, 176.6 mmol)over 30 min at RT and the reaction mixture was stirred at RT overnight.Acetic acid (17 mL) was added; the solution was concentrated and theresidue was combined with the product of a similar preparation anddissolved in DCM, dried over potassium bicarbonate, filtered, and thefiltrate was evaporated to give the title intermediate (30 g).

(c) (S)-6-((tert-Butyldiphenylsilyloxy)methyl)piperidin-2-one

To a mixture of the product of the previous step (30 g, 232.3 mmol) inDCM (300 mL) was added DIPEA (90 g, 696.6 mmol), 4-dimethylaminopyridine(2.84 g, 23.2 mmol), and tert-butyldiphenylsilyl chloride (95.7 g, 349.3mmol) at 0° C. The reaction mixture was stirred at RT overnight and thenwater was added and the reaction mixture was extracted with EtOAc (4×200mL). The organic layers were combined, dried over Na₂SO₄, evaporated,and the residue was purified by silica gel chromatography (eluting with50-100% EtOAc in petroleum ether) to provide the title intermediate (5g).

(d) (S)-tert-Butyl2-((tert-butyldiphenylsilyloxy)methyl)-6-oxopiperidine-1-carboxylate

The product of the previous step (24.3 g, 66.4 mmol) was dissolved inBoc₂O (72.4 g, 332 mmol) and 4-dimethylaminopyridine (810 mg, 66.4 mmol)was added. The reaction mixture was stirred and refluxed overnight,concentrated and purified by silica gel chromatography (eluting with0-50% EtOAc in petroleum ether) to provide the title intermediate (28g).

(g) (2S)-tert-Butyl2-((tert-butyldiphenylsilyloxy)methyl)-6-hydroxypiperidine-1-carboxylate

To a solution of the product of the previous step (14 g, 30 mmol) intoluene cooled to −50° C. was added 1 M lithium triethylborohydride (36mL) in THF (36 mmol) dropwise over 15 min and the reaction mixture wasstirred for 2 h at −50 to −45° C. Saturated aqueous sodium bicarbonatewas added and the reaction mixture was warmed to 0° C. Hydrogen peroxide(1 mL) was added; the reaction mixture was stirred for 20 min; layerswere separated and the aqueous layer was extracted with EtOAc (2×50 mL).The combined organic layer was washed with water and brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (eluting with 0-20% EtOAc inpetroleum ether) to give the title intermediate (10 g). (m/z):[M-100+H]⁺ calcd for C₁₄H₂₃NO₅ 186.16 found 186.1.

(h) ((2S)-tert-Butyl2-((tert-butyldiphenylsilyloxy)methyl)-6-methoxypiperidine-1-carboxylate

To an ice cold solution of (2S)-tert-butyl2-((tert-butyldiphenylsilyloxy)methyl)-6-hydroxypiperidine-1-carboxylate(2 g, 4.3 mmol) in methanol (20 mL) was added pyridiniump-toluenesulfonate (108 mg, 0.43 mmol). The reaction mixture was warmedto RT and stirred overnight. Triethylamine (87 mg, 0.86 mmol) was added,the reaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel chromatography (eluting with 0-15%EtOAc in petroleum ether), and combined with the product of threesimilar runs to provide the title intermediate (3.5 g).

(i) (S)-tert-Butyl2-((tert-butyldiphenylsilyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate

A mixture of ((2S)-tert-butyl2-((tert-butyldiphenylsilyloxy)methyl)-6-methoxypiperidine-1-carboxylate(9 g, 18.6 mmol) and ammonium chloride (150 mg, 2.8 mmol) was heated at150° C. under reduced pressure (50 mbar) for 2 h, cooled to RT, andpurified by silica gel chromatography (eluting with 0-10% EtOAc inpetroleum ether) to provide the title intermediate (7.2 g).

(j) (1R,3S,6S)-tert-Butyl3-((tert-butyldiphenylsilyloxy)methyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate

To an ice cold solution of (S)-tert-butyl2-((tert-butyldiphenylsilyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate(3.6 g, 8.0 mmol) in DCM (40 mL) was added a 1 M solution of diethylzinc(9.0 mL) followed by diiodomethane (3.2 g, 12.0 mmol) over 15 min. Thereaction mixture was stirred for 30 min at 0° C., warmed to RT andstirred for 3 h. The pH of the reaction mixture was adjusted to pH 8with saturated aqueous sodium bicarbonate. The layers were separated andthe aqueous layer was extracted with DCM. The combined organic layerswere washed with brine, dried over Na₂SO₄, concentrated under reducedpressure, purified by silica gel chromatography (eluting with 0-15%EtOAc in petroleum ether) and combined with the product of a similar runto provide the title intermediate (4.5 g) as a colorless gummy liquid.

(k) (1R,3S,6S)-tert-Butyl3-(hydroxymethyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate

To an ice cold solution of the product of the previous step (4.5 g, 9.7mmol) in dry THF (50 mL) was added tetra-n-butylammonium fluoride (4.0g, 19.4 mmol). The reaction solution was warmed to RT, stirred for 12 h,and concentrated under reduced pressure. The residue was dissolved inDCM (50 mL) and washed with water (3×50 mL). The organic layer waswashed with brine, dried over Na₂SO₄, evaporated, and purified by silicagel chromatography (eluting with 0-10% methanol in DCM) to give thetitle intermediate (2.0 g).

(l) (1R,3S,6S)-2-Aza-bicyclo[4.1.0]heptane-2,3-dicarboxylic acid2-tert-butyl ester

To a solution of sodium periodate (15.5 g, 72.6 mmol) in water (80 mL)was added a solution of (1R,3S,6S)-tert-butyl3-(hydroxymethyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate (5.5 g, 24.2mmol) in ACN (60 mL) and carbon tetrachloride (60 mL). Ruthenium(III)chloride (246 mg, 1.21 mmol) was added immediately and the reactionmixture was stirred vigorously for 75 min at RT, diluted with water (80mL), filtered, and extracted with DCM (3×100 mL). The combined organicphase was washed with brine, dried over Na₂SO₄, and concentrated undervacuum to provide crude product (4.75 g) as a light charcoal-colorsolid. The crude product was dissolved in EtOAc (20 mL) with heating andallowed to stand at RT with seeding. After about 15 min, rapid crystalformation was observed. About 1 h later, hexane (10 mL) was added andthe mixture was refrigerated overnight, filtered, washed with 2:1ice-water-cooled hexanes:EtOAc (50 mL) and dried under high vacuum toprovide the title intermediate (1.9 g) ([a]_(D)=−135.2) The motherliquid was re-crystallized to provide additional product (300 mg)([a]_(D)=−142.6). ¹H NMR: (DMSO-d₆, 400 MHz) δ (ppm) 4.1 (m, 1H), 2.60(m, 1H), 1.70 (m, 1H), 1.30 (m, 3H), 1.17 (m, 9H), 0.96 (m, 1H), 0.50(m, 1H), 0.0 (m, 1H)

Example 1[(S)-1-((S)-2-{4-[5′-Chloro-4′-({6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-4-methyl-2,5-dihydro-pyrrole-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

(a)(R)-4-[5-(5-Chloro-2-trifluoromethoxy-4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl]-1H-imidazol-4-yl}-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

To a solution of[(S)-2-Methyl-1-((S)-4-methyl-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2,5-dihydro-pyrrole-1-carbonyl)-propyl]-carbamicacid methyl ester (100 mg, 0.20 mmol, Preparation 4) and(R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester (110 mg, 0.19 mmol) dissolved in toluene (1.18 mL)and water (0.43 mL) was added potassium carbonate (127 mg, 0.92 mmol).The reaction mixture was sparged under nitrogen for 15 min andPd(dppf)Cl₂ CH₂Cl₂ (13.55 mg, 0.017 mmol) was added and the reactionmixture was sparged with nitrogen and heated to 90° C. overnight, cooledto RT, diluted with EtOAc and washed with water and brine to produce adark colored solid, which was purified by silica gel chromatography (12g silica, EtOAc/hexanes 40 to 100%) to produce the title intermediate(51 mg, 31% yield) as a yellowish colored solid. (m/z): [M+H]⁺ calcd forC₄₄H₅₀ClF₃N₈O₇ 895.34 found 895.3.

(b)((S)-1-{(S)-2-[4-(5′-Chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methyl-2,5-dihydro-pyrrole-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

The product of the previous step was treated with 4 M HCl in 1,4-dioxane(0.92 mL) and HCl (0.28 mL) and the reaction mixture was stirred at RTfor 1 h, concentrated and evaporated with ethyl acetate (2×) to producethe tri-HCl salt of the title intermediate (56 mg, 34% yield). (m/z):[M+H]⁺ calcd for C₃₉H₄₂ClF₃N₈O₅ 795.29 found 795.3.

(c)[(S)-1-((S)-2-{4-[5′-Chloro-4′-({6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-4-methyl-2,5-dihydro-pyrrole-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

The product of the previous step (10 mg, 0.011 mmol) was dissolved inDMA (1 mL) and then DIPEA (9.63 μL, 0.055 mmol) was added followed by2,2-dimethylpropionyl chloride (1.33 mg, 0.011 mmol) and the reactionmixture was stirred at RT overnight, concentrated by rotary evaporation,dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reversephase HPLC to provide the di-TFA salt of the title compound (7 mg, 60%yield). (m/z): [M+H]⁺ calcd for C₄₄H₅₀ClF₃N₈O₆ 879.35 found 879.8.

Example 2((S)-1-{(S)-2-[4-(5′-Chloro-4′-{[6-((R)-4-(S)-2,2-dimethylcyclopropanecarbonyl-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methyl-2,5-dihydro-pyrrole-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of 0.5 M of (S)-(+)-2,2-dimethylcyclopropane carboxylicacid in DMA (26.5 μL, 0.013 mmol) in DMA (1 mL) was added HATU (5.04 mg,0.013 mmol). The reaction mixture was stirred at RT for 20 min and theproduct of Example 1 step (b) (10 mg, 0.011 mmol) was then addedfollowed by DIPEA (9.63 μL, 0.055 mmol) and the reaction mixture wasstirred at RT overnight, concentrated by rotary evaporation, dissolvedin 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC toprovide the di-TFA salt of the title compound (7 mg, 55% yield). (m/z):[M+H]⁺ calcd for C₄₅H₅₀ClF₃N₈O₆ 891.35 found 891.8.

Following the procedures of Examples 1 and 2, the intermediate ofPreparation 7 was used to prepare the compounds of Examples 3 and 4.

Example 3[(S)-1-((S)-2-{4-[5′-Chloro-4′-({6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-4-cyclopropyl-2,5-dihydro-pyrrole-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

(0.011 mmol scale, 7 mg, 59% yield) (m/z): [M+H]⁺ calcd forC₄₆H₅₂ClF₃N₈O₆ 905.37 found 905.8.

Example 4((S)-1-{(S)-2-[4-(5′-Chloro-4′-{[6-((R)-4-(S)-2,2-dimethylcyclopropanecarbonyl-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-4-cyclopropyl-2,5-dihydro-pyrrole-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(0.011 mmol scale, 7 mg, 59% yield) (m/z): [M+H]⁺ calcd forC₄₇H₅₂ClF₃N₈O₆ 917.37 found 917.8.

Example 5((S)-1-{(R)-5-[4-(5′-Chloro-4′-{[6-((R)-4-(S)-2,2-dimethylcyclopropanecarbonyl-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a)(R)-4-[5-(5-Chloro-4′-{2-[(R)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-3,3-dimethyl-[1,3]azasilolidin-5-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

To a solution of[[(5)-1-((R)-3,3-dimethyl-5-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-[1,3]azasilolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methylester (51.6 mg, 0.096 mmol; Preparation 11) and(R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester (56.7 mg, 0.096 mmol) dissolved in toluene (0.61mL) and water (0.24 mL) was added potassium carbonate (66.0 mg, 0.48mmol). The reaction mixture was sparged under nitrogen for 15 min andPd(dppf)Cl₂CH₂Cl₂ (7.02 mg, 0.009 mmol) was added. The reaction mixturewas sparged with nitrogen and heated to 90° C. overnight, cooled to RT,diluted with EtOAc, and washed with water and brine to produce a darkcolored oil. The residue was purified by silica gel chromatography (12 gsilica, 0% to 100% EtOAc/hexane) to produce the title intermediate as ayellowish solid (23 mg; 26% yield) (m/z): [M+H]⁺ calcd forC₄₄H₅₄ClF₃N₈O₇Si 927.35 found 927.4.

(b)((S)-1-{(R)-5-[4-(5′-Chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

The product of the previous step was treated with 4 M HCl in 1,4-dioxane(0.47 mL, 1.91 mmol) and HCl (0.17 mL) and stirred at RT for 1 h,concentrated, and evaporated with ethyl acetate (2×) to produce thetri-HCl salt of the title intermediate. (m/z): [M+H]⁺ calcd forC₃₉H₄₆ClF₃N₈O₅Si 827.30 found 827.3.

(c)((S)-1-{(R)-5-[4-(5′-Chloro-4′-{[6-((R)-4-(S)-2,2-dimethylcyclopropanecarbonyl-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of 0.5 M of (S)-(+)-2,2-dimethylcyclopropane carboxylicacid in DMA (30.7 μL, 0.015 mmol) dissolved in DMA (1 mL) was added HATU(5.84 mg, 0.015 mmol). The reaction mixture was stirred at RT for 20 minand then the product of the previous step (12 mg, 0.013 mmol) was addedfollowed by DIPEA (11.2 μL, 0.064 mmol). The reaction mixture wasstirred at RT overnight, concentrated by rotary evaporation, dissolvedin 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC toprovide the di-TFA salt of the title compound (5 mg, 35% yield). (m/z):[M+H]⁺ calcd for C₄₅H₅₄ClF₃N₈O₆Si 923.36 found 923.8.

Example 6[(S)-1-((R)-5-{4-[5′-Chloro-4′-({6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-3,3-dimethyl-[1,3]azasilolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

The intermediate of Example 5 step (b) was reacted with2,2-dimethylpropanyl chloride under standard conditions to provide thedi-TFA salt of the title compound. (0.013 mmol scale, 5 mg, 33% yield)(m/z): [M+H]⁺ calcd for C₄₄H₅₄ClF₃N₈O₆Si 911.36 found 911.8.

Example 7[(S)-1-((R)-5-{4-[4′-({6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-3,3-dimethyl-[1,3]azasilolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

By a procedure analogous to that of Examples 5 and 6,((S)-1-{(R)-5-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester 3 HCl was reacted with 2,2-dimethylpropanyl chlorideto provide the di-TFA salt of the title compound. (0.013 mmol scale, 6.5mg, 46% yield) (m/z): [M+H]⁺ calcd for C₄₄H₅₅F₃N₈O₆Si 877.40 found877.8.

Example 8[(S)-1-((2S,4S)-2-{7-[5-Chloro-4-({6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2-trifluoromethoxy-phenyl]-3H-naphtho[1,2-d]imidazol-2-yl}-4-methyl-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

(a)(R)-4-[5-(2-Chloro-4-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphtho[1,2-d]imidazol-7-yl}-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

To a solution of(R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester (110 mg, 0.19 mmol) and((S)-2-methyl-1-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester (100 mg, 0.19 mmol) dissolved in toluene (1.19 mL) andwater (0.43 mL) was added potassium carbonate (128 mg, 0.93 mmol). Thereaction mixture was sparged with nitrogen for 15 min and Pd(dppf)Cl₂CH₂Cl₂ (13.6 mg, 0.017 mmol) was added. The reaction mixture was spargedwith nitrogen, heated at 90° C. overnight, cooled to RT, diluted withEtOAc and washed with water and brine to produce a dark colored oil,which was purified by silica gel chromatography (24 g silica, 40% to100% EtOAc/hexane) to produce the title intermediate (101 mg; 59% yield)as a yellow solid. (m/z): [M+H]⁺ calcd for C₄₆H₅₂ClF₃N₈O₆ 921.36 found921.3.

(b)((S)-1-{(2S,4S)-2-[7-(5-Chloro-4-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2-trifluoromethoxy-phenyl)-3H-naphtho[1,2-d]imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

The product of the previous step was treated with 4 M HCl in 1,4-dioxane(0.93 mL) and HCl (0.28 mL) and the reaction mixture was stirred at RTfor 1 h, concentrated, and evaporated with ethyl acetate (2×) to producethe tri-HCl salt of the title intermediate. (m/z): [M+H]⁺ calcd forC₄₁H₄₄ClF₃N₈O₅ 821.31 found 821.3.

(c)[(S)-1-((2S,4S)-2-{7-[5-Chloro-4-({6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2-trifluoromethoxy-phenyl]-3H-naphtho[1,2-d]imidazol-2-yl}-4-methyl-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

The product of the previous step (12.0 mg, 0.013 mmol) was dissolved inDMA (1 mL) and then DIPEA (11.2 μL, 0.065 mmol) was added followed by2,2-dimethylpropanoyl chloride (1.6 mg, 0.013 mmol) and left to stir atroom temperature overnight. The reaction mixture was concentrated byrotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) andpurified by reverse phase HPLC to provide the di-TFA salt of the titlecompound (9.5 mg, 65% yield). (m/z): [M+H]⁺ calcd for C₄₆H₅₂ClF₃N₈O₆905.37 found 905.8.

Example 9((S)-1-{(2S,4S)-2-[7-(5-Chloro-4-{[6-((R)-4-cyclopropanecarbonyl-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2-trifluoromethoxy-phenyl)-3H-naphtho[1,2-d]imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

The intermediate of Example 7 step (b) was reacted with 0.5 Mcyclopropanecarbonyl chloride in DMA to provide the di-TFA salt of thetitle compound. (0.013 mmol scale, 9.6 mg, 67% yield) (m/z): [M+H]⁺calcd for C₄₅H₄₈ClF₃N₈O₆ 889.33 found 889.8.

Example 10[(S)-1-((2S,4S)-2-{7-[5-Chloro-4-({6-[(R)-4-((S)-2,2-dimethylcyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2-trifluoromethoxy-phenyl]-3H-naphtho[1,2-d]imidazol-2-yl}-4-methyl-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

The intermediate of Example 7 step (b) was reacted with 0.5 M(S)-(+)-2,2-dimethylcyclopropane carboxylic acid in DMA to provide thedi-TFA salt of the title compound. (0.013 mmol scale, 9.1 mg, 62% yield)(m/z): [M+H]⁺ calcd for C₄₇H₅₂ClF₃N₈O₆ 917.37 found 917.8.

Example 11[(S)-1-((2S,5S)-2-{4-[5′-Chloro-4′-({6-[(R)-4-(3-hydroxy-2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-5-methyl-piperidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

(a)(R)-4-[4-(5-Chloro-4′-{2-[(2S,5S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-5-methyl-piperidin-2-yl]-3H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

To a solution of[(S)-2-methyl-1-((2S,5S)-5-methyl-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-piperidine-1-carbonyl)-propyl]-carbamicacid methyl ester (100 mg, 0.19 mmol) and(R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester (113 mg, 0.19 mmol) dissolved in toluene (1.22 mL)and water (0.45 mL) was added potassium carbonate (132 mg, 0.95 mmol).The reaction mixture was sparged under nitrogen for 15 min. Pd(dppf)Cl₂CH₂Cl₂ (14 mg, 0.017 mmol) was added and the reaction mixture wassparged with nitrogen, heated at 90° C. overnight, cooled to RT, dilutedwith EtOAc, filtered through a combined pad of Celite® and silica gel,flushed several times with EtOAc, and washed with water and brine toproduce a dark colored oil. The residue was purified by silica gelchromatography (12 g silica, 40% to 100% EtOAc/hexane) to produce thetitle intermediate (48 mg, 28% yield) as a yellowish solid. m/z): [M+H]⁺calcd for C₄₅H₅₄ClF₃N₈O₇ 911.38 found 911.3.

(b)((S)-1-{(2S,5S)-2-[4-(5′-Chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-5-methyl-piperidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

The product of the previous step (48 mg) was treated with 4 M HCl in1,4-dioxane (0.95 mL) and HCl (0.29 mL) and the reaction mixture wasstirred at RT for 1 h, concentrated, and evaporated with ethyl acetate(2×) to produce the tri-HCl salt of the title intermediate. m/z): [M+H]⁺calcd for C₄₀H₄₆ClF₃N₈O₅ 811.32 found 811.3.

(c)[(S)-1-((2S,5S)-2-{4-[5′-Chloro-4′-({6-[(R)-4-(3-hydroxy-2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-5-methyl-piperidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of 2,2-dimethyl-3-hydroxypropionic acid (1.5 mg, 0.013mmol) in DMA (1 mL) was added HATU (5.0 mg, 0.013 mmol). The reactionmixture was stirred at RT for 20 min and then the product of theprevious step (10 mg, 0.011 mmol) was added followed by DIPEA (11.7 μL,0.067 mmol). The reaction mixture was stirred at RT overnight,concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water(1.5 mL) and purified by reverse phase HPLC to provide the di-TFA saltof the title compound (5.3 mg, 53% yield). (m/z): [M+H]⁺ calcd forC₄₅H₅₄ClF₃N₈O₇ 911.38 found 911.8.

Example 12((S)-1-{(S)-4-Cyclopropyl-2-[4-(4′-{6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridin-3-ylcarbamoyl}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-2,5-dihydro-pyrrole-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a){(S)-1-[(S)-4-Cyclopropyl-2-(4-{4′-[6-((R)-2-methyl-piperazin-1-yl)-pyridin-3-ylcarbamoyl]-2′-trifluoromethoxy-biphenyl-4-yl}-1H-imidazol-2-yl)-2,5-dihydro-pyrrole-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

To the mixture of4′-{2-[(S)-4-cyclopropyl-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-2,5-dihydro-1H-pyrrol-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylicacid TFA (70 mg, 0.096 mmol; Preparation 15) and HATU (40 mg, 0.11 mmol)in DMF (1 mL) at RT was added(R)-4-(5-amino-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acidtert-butyl ester (31 mg, 0.11 mmol) and DIPEA (83.9 μL, 0.48 mmol). Thereaction mixture was stirred at RT for 1 h, and partitioned betweenEtOAc (5 mL) and water (2 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated to give a brownish red oil, whichwas treated with a mixture of DCM (1.7 mL) and TFA (1.7 mL) at RT for 1hour. The reaction mixture was concentrated, diluted with water (6 mL),filtered and purified by reverse phase HPLC. Desired fractions werecombined and freeze dried to give the tri-TFA salt of the titleintermediate (68 mg, 62% yield) as a white solid. (m/z): [M+H]⁺ calcdfor C₄₁H₄₅F₃N₈O₅ 787.35 found 787.

(b)((S)-1-{(S)-4-Cyclopropyl-2-[4-(4′-{6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridin-3-ylcarbamoyl}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-2,5-dihydro-pyrrole-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of the product of the previous step (11 mg, 0.010 mmol)and DIPEA (8.49 μL, 0.049 mmol) in DMF (0.5 mL) was added2,2-dimethylpropanoyl chloride (1.20 μL, 0.010 mmol) and the reactionmixture was stirred at RT overnight, concentrated by rotary evaporation,dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reversephase HPLC to provide the di-TFA salt of the title compound (9.4 mg).(m/z): [M+H]⁺ calcd for C₄₆H₅₃F₃N₈O₆ 871.40 found 871.8.

Example 13((S)-1-{(2S,4S)-2-[7-(4-{6-[(R)-4-(2,2-Dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridin-3-ylcarbamoyl}-2-trifluoromethoxy-phenyl)-3H-naphth[1,2-d]imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a)(R)-4-[5-(4-{2-[(2S,4S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphth[1,2-d]imidazol-7-yl}-3-trifluoromethoxy-benzoylamino)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

A solution of4-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphth[1,2-d]imidazol-7-yl}-3-trifluoromethoxy-benzoicacid TFA (136 mg, 0.19 mmol; Preparation 17) and HATU (86 mg, 0.23 mmol)in DMA (3 mL) was stirred for 10 min, then(R)-4-(5-amino-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acidtert-butyl ester (55 mg, 0.19 mmol), and DIPEA (98 μL, 0.56 mmol) wereadded. The resulting mixture was stirred at RT for 1 h, concentrated,and purified by silica gel chromatography (EtOAc/hexane 20 to 100%) togive the title intermediate (158 mg, 95% yield). (m/z): [M+H]⁺ calcd forC₄₆H₅₃F₃N₈O₇ 887.40 found 887.4.

(b){(S)-2-Methyl-1-[(2S,4S)-4-methyl-2-(7-{4-[6-((R)-2-methyl-piperazin-1-yl)-pyridin-3-ylcarbamoyl]-2-trifluoromethoxy-phenyl}-3H-naphth[1,2-d]imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester

The product of the previous step was treated with 4.0 M of HCl in1,4-dioxane (2 mL) for 1 h and concentrated by rotary evaporation toprovide the tri-HCl salt of the title intermediate (157 mg, 94% yield).(m/z): [M+H]⁺ calcd for C₄₁H₄₅F₃N₈O₅ 787.35 found 787.3.

(c)((S)-1-{(2S,4S)-2-[7-(4-{6-[(R)-4-(2,2-Dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridin-3-ylcarbamoyl}-2-trifluoromethoxy-phenyl)-3H-naphth[1,2-d]imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of the product of the previous step (15 mg, 0.017 mmol)and DIPEA (14.6 μL, 0.084 mmol) in DMA (0.5 mL) was added2,2-dimethylpropionyl chloride (2.06 μL, 0.017 mmol. The resultingmixture was stirred at RT overnight, concentrated by rotary evaporation,dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reversephase HPLC to provide the di-TFA salt of the title compound (7.8 mg).(m/z): [M+H]⁺ calcd for C₄₆H₅₃F₃N₈O₆ 871.40 found 871.8.

Example 14[(S)-2-((2S,4S)-2-{7-[4-({6-[(R)-4-(2,2-Dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-5-chloro-2-trifluoromethoxy-phenyl]-3H-naphtho[1,2-d]imidazol-2-yl}-4-methyl-pyrrolidin-1-yl)-2-oxo-1-(tetrahydropyran-4-yl)-ethyl]-carbamicacid methyl ester

(a)(R)-4-{5-[2-Chloro-4-(2-{(2S,4S)-1-[(S)-2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-4-methyl-pyrrolidin-2-yl}-3H-naphtho[1,2-d]imidazol-7-yl)-5-trifluoromethoxy-phenylcarbamoyl]-pyridin-2-yl}-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

To a mixture of[(S)-2-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-naphth[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester (80 mg, 0.10 mmol; Preparation 23) and(R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester (85 mg, 0.14 mmol) dissolved in toluene (0.92 mL)and water (0.34 mL) was added potassium carbonate (103 mg, 0.75 mmol).The reaction mixture was sparged under nitrogen and Pd(dppf)Cl₂ CH₂Cl₂(7.0 mg, 0.009 mmol) was added and the reaction mixture was heated to90° C. overnight, cooled to RT, filtered through a combined pad ofCelite® and silica gel and washed with EtOAc. The filtrate was washedwith water and brine to produce a brownish colored solid, which waspurified by silica chromatography (12 g column, 5-100% EtOAc/hexanes) toproduce the title intermediate (89 mg, 60% yield) as a light coloredsolid. (m/z): [M+H]⁺ calcd for C₄₈H₅₄ClF₃N₈O₈ 963.37 found 963.5.

(b)[(S)-2-{(2S,4S)-2-[7-(5-Chloro-4-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2-trifluoromethoxy-phenyl)-3H-naphth[1,2-d]imidazol-2-yl]-4-methyl-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

The solid from the previous step was treated with 4 M HCl in 1,4-dioxane(1 mL) and stirred at RT overnight, concentrated, and evaporated withEtOAc (2×) to produce the tri-HCl salt of the title intermediate (80 mg,60% yield) as a yellow solid. (m/z): [M+H]⁺ calcd for C₄₃H₄₆ClF₃N₈O₆863.32 found 863.6.

(c)[(S)-2-((2S,4S)-2-{7-[4-({6-[(R)-4-(2,2-Dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-5-chloro-2-trifluoromethoxy-phenyl]-3H-naphtho[1,2-d]imidazol-2-yl}-4-methyl-pyrrolidin-1-yl)-2-oxo-1-(tetrahydropyran-4-yl)-ethyl]-carbamicacid methyl ester

To a solution of the product of the previous step (23 mg, 0.024 mmol)and DIPEA (29 μL, 0.16 mmol) dissolved in DMF (0.5 mL) was added2,2-dimethylpropionyl chloride (2.9 μL, 0.024 mmol). The reactionmixture was stirred at RT for 1 h, concentrated, dissolved in 1:1 aceticacid:water (1.5 mL), and purified by reverse-phase HPLC to provide thedi-TFA salt of the title compound (14.1 mg). (m/z): [M+H]⁺ calcd forC₄₈H₅₄ClF₃N₈O₇ 947.38 found 947.8.

Example 15[(S)-2-((2S,4S)-2-{7-[4-({6-[(R)-4-(3-Hydroxy-2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-5-chloro-2-trifluoromethoxy-phenyl]-3H-naphtho[1,2-d]imidazol-2-yl}-4-methyl-pyrrolidin-1-yl)-2-oxo-1-(tetrahydropyran-4-yl)-ethyl]-carbamicacid methyl ester

The intermediate of Example 14 step (b) was reacted at the 0.024 molscale with 2,2-dimethyl-3-hydroxypropionic acid and HATU (1.5 equiv) toprovide the di-TFA salt of the title compound (13.9 mg). (m/z): [M+H]⁺calcd for C₄₈H₅₄ClF₃N₈O₈ 963.37 found 963.8.

Using similar synthetic procedures, the compounds of Tables 1 to 5 wereprepared, where a blank in any column denotes hydrogen.

TABLE 1

Ex Calc Found No. * R¹¹ R^(7a) R^(7d) R⁹ Formula [M + H]⁺ [M + H]⁺ 1-1

C₄₄H₅₄N₈O₅ 775.42 775.4 1-2

C₄₂H₄₈N₁₀O₅ 773.38 773.2 1-3 —NHCH₃ C₄₀H₄₉N₉O₅ 736.39 736.2 1-4 (S) CH₃OCF₃ Cl

C₄₆H₅₄ClF₃N₈O₆ 907.38 907.8 1-5 (S) CH₃ OCF₃ Cl

C₄₅H₅₄ClF₃N₈O₆ 895.38 895.8 1-6 (R) CH₃ OCF₃ Cl

C₄₅H₅₄ClF₃N₈O₇ 911.38 911.8 1-7 (R) CH₃ OCF₃ Cl

C₄₆H₅₄ClF₃N₈O₆ 907.38 907.8 1-8 (R) CH₃ OCF₃ Cl

C₄₅H₅₄ClF₃N₈O₆ 895.38 895.8

TABLE 2

Ex Calc Found No. R⁴ * R^(8d) R⁹ Formula [M + H]⁺ [M + H]⁺ 2-1  CH₃ (S)CH₃

C₄₄H₄₉F₃N₈O₆ 843.37 843.8 2-2  CH₃ (S) CH₃ —NHCH₃ C₄₂H₄₈F₃N₉O₆ 832.37832.8 2-3  CH₃ (S) CH₃

C₄₅H₅₃F₃N₈O₆ 859.40 859.8 2-4  CH₃ (S) CH₃

C₄₆H₅₃F₃N₈O₆ 871.40 871.8 2-5  CH₃ (S) CH₃

C₄₄H₅₀F₃N₉O₇ 874.38 874.8 2-6  CH₃ (S) CH₃

C₄₆H₅₃F₃N₈O₇ 887.40 887.8 2-7  CH₃ (S) CH₃

C₄₄H₄₇Cl₂F₃N₈O₆ 911.30 911.8 2-8  CH₃ (S) CH₃

C₅₀H₆₀F₃N₉O₇ 956.46 957.0 2-9  CH₃ (S) CH₃

C₄₉H₅₈F₃N₉O₇ 942.44 943.0 2-10 cPr

C₄₇H₄₇D₆F₃N₈O₆ 889.44 890.0 2-11 cPr

C₄₇H₅₃F₃N₈O₆ 883.40 883.8

TABLE 3

Ex Calc Found No. R^(7a) * R^(8d) R⁹ Formula [M + H]⁺ [M + H]⁺ 3-1 

C₄₅H₅₄N₈O₆ 803.42 803.8 3-2 

C₄₆H₅₄N₈O₅ 799.42 799.1 3-3  —NHCH₃ C₄₂H₄₉N₉O₅ 760.39 760.8 3-4  OCF₃

C₄₅H₄₉F₃N₈O₆ 855.37 855.8 3-5  OCF₃

C₄₇H₅₃F₃N₈O₆ 883.40 884.0 3-6  OCF₃

C₄₇H₄₇D₆F₃N₈O₆ 889.44 888.8 3-7  OCF₃

C₄₄H₅₀F₃N₉O₆ 858.38 858.8 3-8  OCF₃ (S) CH₃

C₄₈H₄₉D₆F₃N₈O₆ 903.46 904.0 3-9  OCF₃ (S) CH₃

C₄₇H₅₅F₃N₈O₆ 885.42 886.0 3-10 OCF₃ (S) CH₃

C₄₅H₅₂F₃N₉O₆ 872.40 872.8 3-11 OCF₃ (S) CH₃

C₄₆H₅₁F₃N₈O₆ 869.39 869.8 3-12 OCF₃ (S) CH₃

C₄₈H₅₅F₃N₈O₆ 897.42 898.0 3-13 OCF₃

C₄₇H₅₆F₃N₉O₆ 900.43 900.8 3-14 OCF₃

C₅₀H₅₈F₃N₉O₇ 954.44 955.0 3-15 OCF₃

C₄₇H₅₁F₃N₈O₆ 881.39 881.8

TABLE 4

Ex Calc Found No. R¹ R^(7a) R^(7d) R⁹ Formula [M + H]⁺ [M + H]⁺ 4-1

OCF₃

C₄₈H₅₅F₃N₈O₉ 945.40 945.6 4-2

OCF₃

C₄₈H₅₅F₃N₈O₈ 929.41 929.6 4-3

C₄₉H₅₈N₈O₆ 855.45 855.6 4-4

C₄₈H₅₆N₈O₇ 857.43 857.6 4-5

C₄₆H₅₆N₈O₅ 801.44 801.6

TABLE 5 Ex Calc Found No. Formula [M + H]⁺ [M + H]⁺ 5-1 

C₄₅H₅₄N₈O₅ 787.42 787.4 5-2 

C₄₈H₅₄F₄N₈O₇ 931.41 931.8 5-3 

C₄₈H₅₄F₄N₈O₈ 947.40 947.8 5-4 

C₄₇H₅₄ClF₃N₈O₇ 935.38 935.8 5-5 

C₄₅H₅₂ClF₃N₈O₆ 893.37 893.8 5-6 

C₄₈H₅₄ClF₃N₈O₇ 947.38 948.0 5-7 

C₄₈H₅₄ClF₃N₈O₈ 963.37 964.0 5-8 

C₄₆H₅₂ClF₃N₈O₆ 905.37 905.8 5-9 

C₄₅H₅₂ClF₃N₈O₇ 909.36 909.8 5-10

C₄₅H₅₂ClF₃N₈O₆ 893.37 893.8 5-11

C₄₆H₅₄ClF₃N₈O₆ 907.38 907.6 5-12

C₄₈H₅₆ClF₃N₈O₇ 949.39 949.6Biological Assays

The hepatitis C virus has been classified into six major differentgenotypes on the basis of nucleotide sequence, and further divided intosubtypes within genotypes. Compounds of the invention demonstratedinhibition of HCV replication in one or more of the following HCVreplicon assays.

Assay 1: HCV Genotype 1b Replicon Assay

The HCV genotype 1b replicon cell line was obtained from Apath LLC(Brooklyn, N.Y.) (APC144; Huh7 cell background). This subgenomicreplicon contains the N-terminus of the HCV core protein fused to theneomycin-resistance selectable marker. The EMCV IRES lies downstream anddrives expression of humanized Renilla luciferase fused to thenon-structural proteins NS3-NS5B. This cell line was used to determinecompound potency using the luciferase activity readout as a measurementof compound inhibition of replicon levels.

Cells were grown at 37° C. in a 5% CO₂ humidified incubator in DMEM(Invitrogen) with 10% FBS (HyClone), 1×NEAA (Invitrogen), 1× Pen-Strep(Invitrogen), and 500 g/mL G418 (Invitrogen). On day 1 of the assay,cells were plated at 10,000 cells/well in white 96-well tissue cultureplates (Costar) in 200 μL media lacking G418. Four hours later, once thecells have adhered, the media was removed and replaced with media (noG418) containing dose-responses of test compounds. Compounds wereinitially diluted in DMSO and then diluted another 200× in media tobring the final DMSO concentration down to 0.5%. The cells wereincubated with test compounds for 48 hours. At the end of the incubationperiod, media and compound were removed from the plates and theluciferase activity was determined using Promega Renilla-Glo reagents.

To analyze the data, the luciferase activity was plotted vs. thecompound concentration, and EC₅₀ values were determined from a4-parameter robust fit model with the GraphPad Prism software package(GraphPad Software, Inc., San Diego, Calif.). Results are expressed asthe negative decadic logarithm of the EC₅₀ value, pEC₅₀.

Test compounds having a higher pEC₅₀ value in this assay show greaterinhibition of HCV genotype 1b replication. Compounds of the inventiontested in this assay typically exhibited pEC₅₀ values between about 7and about 12.

Assay 2: HCV Genotype 1a Replicon Assay

The HCV genotype 1a replicon cell line was obtained from Apath LLC(APC89; Huh7.5 cell background). This subgenomic replicon contains theN-terminus of the HCV core protein fused to the neomycin-resistanceselectable marker. The EMCV IRES lies downstream and drives expressionof the non-structural proteins NS3-NS5B. Compound potencies weredetermined using the NS3-specific protease activity in lysates as ameasurement of compound inhibition of replicon levels.

Cells were grown at 37° C. in a 5% CO₂ humidified incubator in DMEM(Invitrogen) with 10% FBS (HyClone), 1×NEAA (Invitrogen), 1× Pen-Strep(Invitrogen), and 850 g/mL G418 (Invitrogen). On day 1 of the assay,cells were plated at 15,000 cells/well in black 96-well tissue cultureplates (Costar) in 200 μL media lacking G418. Four hours later, once thecells had adhered, the media was removed and replaced with media (noG418) containing dose-responses of test compounds. Compounds wereinitially diluted in DMSO and then diluted another 200× in media tobring the final DMSO concentration down to 0.5%. The cells wereincubated with test compounds for 48 or 72 hours. At the end of theincubation period, media and compound were removed from the plates.

To determine the NS3-specific protease activity in lysates, the cellswere lysed at room temperature in 50 μL/well of 50 mM Hepes pH 7.5, 150mM NaCl, 15% Glycerol, 0.15% Triton X-100, 10 mM DTT for 20 minutes withshaking. 50 μL of an NS3/4a protease-specific FRET substrate (AnaspecRET S1 Cat#22991) was then added to the wells at a final concentrationof 15 μM. The plates were incubated at 37° C. for 20 minutes, whichcorresponds to a timepoint at which the protease activity is still inthe linear phase. Protease activity was determined by measuringfluorescence (Excitation: 340 nm; Emission: 509 nm).

To analyze the data, the fluorescence was plotted vs. the compoundconcentration, and EC50 values were determined from a 4-parameter robustfit model using GraphPad Prism software. Compounds of the inventiontested in this assay typically exhibited pEC₅₀ values between about 6and about 11.5.

Assay 3: Replicon Assays Against Resistant Mutants

To create replicon cells with resistant mutations of interest, themutation was first introduced into the parental plasmid by site-directedmutagenesis. Mutations in genotype 1b included L31V, Y93H, and theL31V/Y93H double mutant. Mutations in genotype 1a included Q30R andL31V. The replicon plasmid was then linearized and in vitro transcribedto RNA. The RNA was used to stably transfect Huh7 cells byelectroporation, and new cell lines were selected with 500 g/mL G418.Potencies of test compounds against these mutant cell lines weredetermined as previously described above for the HCV Genotype 1b and 1areplicon assays.

Potencies of test compounds against additional mutations of interestwere determined using transient transfection assays. These mutantsincluded genotype 1a Y93C, Y93H, M28T, Q30E, Q30K, L31M, and Y93N. Themutation was first introduced into the parental plasmid by site-directedmutagenesis. The replicon plasmid was then linearized and in vitrotranscribed to RNA. The RNA was used to transiently transfect Huh-LUNETcells (obtained from ReBLikon GmbH, Schriesheim, Germany) byelectroporation, and the potencies of test compounds against the mutantswere determined as previously described.

Assay 4: Replicon Assays Against NS5A Sequences of Other Genotypes

Potencies of test compounds against NS5A sequences of other genotypeswere determined by creating intergenotypic chimeras. The entire NS5Agene from genotypes 2a, 2b, 3a, 4a, 5a, and 6a, or the nucleotidesequence encoding amino acids 11-118 of NS5A, was subcloned into agenotype 1b replicon. For genotype 2a, intergenotypic chimeras with boththe JFH and the J6 strain were created. In general, NS5A inhibitors havebeen shown to exhibit significantly weaker potency against the J6 straindue to the presence of a naturally occurring L31M sequence variant.Since the majority of genotype 2a sequences in public databases containthe L31M sequence variant, the use of the J6 genotype 2a sequence maybetter reflect the antiviral potency of NS5A inhibitors.

These chimeric replicon plasmids were then linearized and in vitrotranscribed to RNA. The RNA was used to transiently or stably transfectHuh-LUNET cells by electroporation, and the potencies of test compoundsagainst the chimeras were determined as previously described.

Assay Results

All of the compounds of Examples 1 to 15 and Tables 1 to 5 were testedin one or more of the assays described above. For example, the followingresults were obtained in the HCV genotype 1a and 1b replicon assayswhere A represents a pEC₅₀ value between 6 and 8 (EC₅₀ between 1 μM and10 nM), B represents pEC₅₀ between 8 and 9 (EC₅₀ between 1 and 10 nM), Crepresents pEC₅₀ between and 9 and about 10, (EC₅₀ between 1 nM and 0.1nM), and D represents pEC₅₀>10 (EC₅₀<0.1 nM).

TABLE 1 Example Genotype Genotype No. 1a 1b 1 D 2 D 3 D 4 D D 5 D D 6 C7 C D 8 D D 9 D D 10 D D 11 C 12 C 13 D D 14 D D 15 D D 1-1 C D 1-2 B1-3 B 1-4 C 1-5 C 1-6 C 1-7 D 1-8 C

TABLE 2 2-1 C 2-2 C 2-3 C 2-4 D 2-5 C 2-6 C 2-7 C 2-8 B 2-9 C  2-10 D D 2-11 D D

TABLE 3 Example Genotype Genotype No. 1a 1b 3-1 D D 3-2 D 3-3 D 3-4 D3-5 D D 3-6 D 3-7 D 3-8 D 3-9 D  3-10 D  3-11 D  3-12 D  3-13 D  3-14 C 3-15 D

TABLE 4 4-1 D D 4-2 D 4-3 D 4-4 D 4-5 A

TABLE 5 5-1 D D 5-2 D D 5-3 D D 5-4 D 5-5 C 5-6 D D 5-7 D D 5-8 D 5-9 D 5-10 D D  5-11 C  5-12 C

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. Additionally, all publications, patents, andpatent documents cited hereinabove are incorporated by reference hereinin full, as though individually incorporated by reference.

What is claimed is:
 1. A compound formula (II):

wherein the dashed bond in formula II may be present or absent; G is

R¹ is selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, phenyl, C₃₋₆ cycloalkyl,heterocycle, and heteroaryl, wherein C₁₋₆ alkyl is optionallysubstituted with —OR^(a), amino, —SR^(e), heterocycle, or heteroaryl,C₁₋₆ alkoxy is optionally substituted with —OR^(a), and heterocycle isoptionally substituted with —OR^(a) amino, or —C(O)OC₁₋₆ alkyl, or withone or two C₁₋₃ alkyl; R² is selected from hydrogen and C₁₋₆ alkyl; R³is selected from hydrogen, C₁₋₆ alkyl, —C(O)OC₁₋₆ alkyl,—C(O)NR^(b)R^(c), —C(O)C₃₋₆ cycloalkyl, and —S(O)₂ C₁₋₃ alkyl; R⁵ isselected from hydrogen, C₁₋₆ alkyl, —OR^(d) halo, —S(O) C₁₋₃ alkyl,—S(O)₂C₁₋₃ alkyl, NR^(b)R^(c), —CN, and —C(O)NR^(b)R^(c); R⁷ is selectedfrom halo, C₁₋₃ alkyl, and C₁₋₃ alkoxy wherein C₁₋₃ alkyl, and C₁₋₃alkoxy are optionally substituted with one, two, three, four, or fivehalo; R⁸ is C₁₋₃ alkyl, optionally substituted with —OR^(d); R⁹ isselected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, —NR^(f)R^(g),heteroaryl, heterocycle, and —CH₂-heteroaryl; wherein: C₁₋₆ alkyl isoptionally substituted with one or two substituents independentlyselected from —OR^(h), —NR^(j)R^(k), —NHC(O) C₁₋₃ alkyl, —NHC(O)C₃₋₆cycloalkyl, and —NHC(O)O C₁₋₃ alkyl; C₁₋₆ alkoxy is optionallysubstituted with —OR^(h); any C₃₋₆ cycloalkyl is optionally substitutedwith one, two, or three substituents independently selected from C₁₋₃alkyl, halo, —OR^(h), and —CD₃; any heterocycle is optionallysubstituted with one, two, or three substituents independently selectedfrom C₁₋₃ alkyl, halo, —C(O)OC₁₋₃ alkyl, —C(O)C₁₋₆ alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)NH C₁₋₆alkyl, and —C(O)NHC₃₋₆ cycloalkyl; wherein any—C(O)C₁₋₆ alkyl is optionally substituted with —NHC(O)OC₁₋₃ alkyl,—OR^(h) or —NR^(j)R^(k), any heteroaryl is optionally substituted withone or two C₁₋₃ alkyl; R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(h),R^(j), and R^(k) are each independently hydrogen or C₁₋₃ alkyl; R^(g) isselected from hydrogen, C₁₋₆ alkyl, and C₁₋₃cycloalkyl; A_(m) is—NHC(O)— or —C(O)NH—; a is 0, 1, or 2; and b is 0, 1 or 2; or apharmaceutically-acceptable salt or stereoisomer thereof.
 2. Thecompound of claim 1 wherein the compound of formula (II) is a compoundof formula (VIII):


3. The compound of claim 2 wherein: R¹ is selected from C₁₋₆alkyl,phenyl, and tetrahydropyranyl, wherein C₁₋₆alkyl is optionallysubstituted with —OR^(a); R² is hydrogen or C₁₋₆alkyl; R³ is selectedfrom hydrogen, C₁₋₆alkyl, and —C(O)OC₁₋₆alkyl; R⁵ is hydrogen orC₁₋₃alkyl; R⁷ is selected from fluoro, chloro, —CF₃, and —OCF₃; R⁸ ismethyl; R⁹ is selected from C₁₋₆alkyl, optionally substituted with—OR^(h), and C₃₋₄cycloalkyl, optionally substituted with one or twoC₁₋₃alkyl; a is 2; and b is
 1. 4. The compound of claim 1 wherein thecompound of formula (II) is a compound of formula (IX):


5. The compound of claim 4 wherein R¹ is selected from C₁₋₆alkyl,phenyl, and tetrahydropyranyl, wherein C₁₋₆alkyl is optionallysubstituted with —OR^(a); R² is hydrogen or C₁₋₆alkyl; R³ is selectedfrom hydrogen, C₁₋₆alkyl, and —C(O)OC₁₋₆alkyl; R⁵ is hydrogen,C₁₋₃alkyl, or —OR^(h); R⁷ is selected from fluoro, chloro, —CF₃, and—OCF₃; R⁸ is methyl; R⁹ is selected from C₁₋₆alkyl, optionallysubstituted with —OR^(h), and C₃₋₄cycloalkyl, optionally substitutedwith one or two C₁₋₃alkyl; a is 2; and b is
 1. 6. A pharmaceuticalcomposition comprising a compound of claim 1 and apharmaceutically-acceptable carrier.
 7. The pharmaceutical compositionof claim 6 further comprising one or more other therapeutic agentsuseful for treating hepatitis C viral infections.
 8. The pharmaceuticalcomposition of claim 7 wherein the one or more other therapeutic agentsis selected from HCV NS3 protease inhibitors, and HCV NS5B nucleosideand non-nucleoside polymerase inhibitors.
 9. A method of treatinghepatitis C viral infection in a mammal, the method comprisingadministering to the mammal a pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically-acceptable carrier.
 10. Themethod of claim 9 wherein the method further comprises administering oneor more other therapeutic agents useful for treating hepatitis C viralinfections.
 11. The method of claim 10 wherein the one or more othertherapeutic agents is selected from HCV NS3 protease inhibitors, HCVNS5B nucleoside and non-nucleoside polymerase inhibitors, interferonsand pegylated interferons, cyclophilin inhibitors, HCV NS5A inhibitors,and ribavirin and related nucleoside analogs.
 12. A method of inhibitingreplication of the hepatitis C virus in a mammal, the method comprisingadministering to the mammal a pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically-acceptable carrier.
 13. Themethod of claim 12 wherein the method further comprises administering tothe mammal one or more other therapeutic agents useful for inhibitingreplication of the hepatitis C virus in a mammal.
 14. The method ofclaim 13 wherein the one or more other therapeutic agents is selectedfrom HCV NS3 protease inhibitors, HCV NS5B nucleoside and non-nucleosidepolymerase inhibitors, interferons and pegylated interferons,cyclophilin inhibitors, HCV NS5A inhibitors, and ribavirin.